Extended release compositions comprising pyridostigmine

ABSTRACT

Extended release pyridostigmine dosage forms, suitable for maintaining stable plasma concentrations with reduced or minimized initial burst release/dose dumping of pyridostigmine, are provided. The dosage forms include matrix tablets, gastroretentive tablets, and pellets, the latter being suitable for dosing in capsules, tablets, and sachets, as well as for sprinkling on foodstuffs. The disclosure also provides methods for improving patient compliance by administering once-a-day extended release pyridostigmine bromide dosage forms that provide a superior controlled drug release.

1. RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/609,397, filed Oct. 29, 2019, which is a U.S. National Stage patentapplication under 35 U.S.C. § 371 of International Application No.PCT/US2019/037795, filed on Jun. 18, 2019, which claims priority toInternational Application No. PCT/US2018/038118, filed Jun. 18, 2018;U.S. Provisional Patent Application No. 62/725,024, filed Aug. 30, 2018,and U.S. Provisional Patent Application No. 62/826,402, filed Mar. 29,2019, the disclosures of which are hereby incorporated by referenceherein in their entireties.

2. TECHNICAL FIELD

The present disclosure provides extended release pyridostigminecompositions suitable for once-daily administration. The compositionsare administered as a single dosage unit/day (QD) to provide extendedrelease of pyridostigmine bromide for at least about 14 hours (e.g., atleast about 18 hours). Such extended release compositions areparticularly beneficial in overcoming the gastrointestinal (GI) sideeffects experienced with currently pyridostigmine products by providingand maintaining therapeutic plasma concentrations for extended timeperiods, e.g., at least about 14 hours. The extended releasepyridostigmine compositions of the disclosure include matrix tablets,gastroretentive tablets, and pellets, the latter being suitable fordosing in capsules, tablets, and sachets, and for sprinkling onfoodstuffs. In certain embodiments, the gastroretentive compositions ofthe disclosure include an immediate release (IR) portion (comprising animmediate release drug layer) and an extended release (ER) portion. Theimmediate release portion minimizes the lag time seen with the extendedrelease portion alone, while providing drug plasma concentrations thatare sufficient to provide a therapeutic effect; thereduction/elimination of the initial burst release/dose dumping seenwith marketed pyridostigmine products aids in reducing GI side effects.The extended release portion provides and maintains therapeutic plasmaconcentrations of the drug for a period of at least about 14 hours.

3. BACKGROUND

Pyridostigmine bromide is an active cholinesterase inhibitor that doesnot cross the blood-brain barrier. It works by increasing levels ofacetylcholine, a chemical released by motor neurons to activate muscles.It is commonly used in muscle tone recovery in myasthenia gravis (MG),postoperative functional bowel bloating, and urinary retention. It hasalso been approved for combat use by United States military personnel,i.e., pyridostigmine bromide has been approved by the U.S. Food and DrugAdministration (FDA) to increase survival after exposure to Soman “nervegas” poisoning.

The time-to-maximum peak plasma concentration of oral pyridostigmine is1-2 hours and its elimination half-life is about 3-5 hours.Pyridostigmine undergoes hydrolysis by the enzyme cholinesterase and ismetabolized in the liver. It is excreted in the urine as a combinationof unchanged drug and pyridostigmine metabolites. The bioavailability ofpyridostigmine is reported to be about 10-20% (NDA #020414). Due tosuboptimal pharmacokinetics of pyridostigmine, including a shortduration of action, MG patients must take multiple tablets, occasionallymultiple times a day. The patients experience “wearing off” of the drugand worsening of symptoms prior to the next dose, suffer from poortolerability at higher dose levels, and experience difficulty adheringto the required frequent dosing regimen.

The FDA has approved Valeant Pharmaceutical's MESTINON® (pyridostigminebromide injection, suspension, tablets, and extended release (ER)tablets) for the treatment of MG. The MESTINON® injection contains 5mg/ml pyridostigmine bromide; MESTINON® suspension contains 60mg/teaspoon pyridostigmine bromide; MESTINON® tablets contain 60 mgpyridostigmine bromide; and ER MESTINON® TIMESPAN® tablets contain 180mg pyridostigmine bromide. The average daily dose of pyridostigmine isten 60 mg tablets, ten teaspoons of suspension, or between one and three180 mg ER tablets, spaced to provide maximum relief. The ER 180 mgtablets are administered, as 1-3 tablets, depending upon severity of thecondition, once- or twice-daily with an interval of at least 6 hoursbetween doses.

The currently approved ER pyridostigmine products provide an initialburst release/dose dumping, followed by extended release ofpyridostigmine bromide. The approved ER formulations release about35-55% of pyridostigmine after one hour, about 65-85% after four hours,and about 85% after eight hours (in vitro dissolution). As more than40-50% of the drug can be released during first hour with theapproved/marketed ER product, it has limited clinical utility. Presentlymarketed pyridostigmine products are plagued by a spike inconcentration, or dose dumping, while attempting to maintain therapeuticplasma concentrations of the drug for extended periods of time. Initialburst release/dose dumping of the drug is associated with various sideeffects, e.g., nausea, vomiting, diarrhea, abdominal cramps,fasciculations, weakness, increased peristalsis, increased salivation,increased bronchial secretions, miosis, and diaphoresis. Such an initialspike in vivo, causing unwanted side effects, can be compared with invitro release of at least about 50% of the pyridostigmine bromide withintwo hours of dissolution into a dissolution medium comprising 50 mMacetate buffer with 100 mM NaCl.

It is particularly desirable for MG patients to have a constant level ofpyridostigmine to improve therapeutic outcome and quality of life, andto reduce side effects. There remains a need for ER pyridostigminecompositions that are designed to prolong and maintain therapeuticplasma concentration of pyridostigmine, and minimize side effects, bycontrolling the initial burst release/dose dumping of the drug. Thereremains a need in the art for ER pyridostigmine compositions thatprovide a minimal lag time, provide extended release with minimal dosedumping, and maintain a stable therapeutic plasma concentration of thedrug for extended periods of time. There remains a need in the art forextended release pyridostigmine compositions containing an immediaterelease portion to eliminate the lag time, and an extended releaseportion to provide extended release with minimal dose dumping of thedrug; for extended release pyridostigmine compositions that will allowfor reduced frequency of administration of the composition, improvepatient compliance, and reduce side effects associated with an unwantedinitial burst in drug release/dose; and for development of a once-a-dayextended release pyridostigmine compositions that can provide anextended release for at least about 16 hours (preferably about 24hours), and reduce side effects associated with dose dumping of thedrug.

4. SUMMARY

In certain embodiments, the present disclosure provide for agastroretentive dosage form comprising an extended release portion andan immediate release portion, wherein the extended release portioncomprises a core comprising pyridostigmine bromide, an acid, agas-generating agent, and a water-soluble hydrophilic polymer thatswells via imbibition of gastric fluid, and a permeable elastic membranesurrounding the core and comprising a plasticizer, and a copolymer basedon ethyl acrylate, methyl methacrylate, and trimethylammonioethylmethacrylate chloride, and the immediate release portion comprises animmediate release drug layer containing pyridostigmine bromide, andwherein the dosage form provides an extended release, with reducedinitial burst release, of pyridostigmine bromide, for at least about 14hours.

In certain other embodiments, the present disclosure provides for adosage form wherein the reduced initial burst release comprises an invitro release of between about 20% and about 35% of the pyridostigminebromide within 2 hours of dissolution in a dissolution medium comprising50 mM acetate buffer with 100 mM NaCl.

In certain embodiments, the dosage form of the present disclosure floatsin about 40 minutes or less in 50 mM of pH 4.5 buffer with 100 mM NaCl.

In certain embodiments, the dosage form of the present disclosure, whenin contact with gastric fluid, swells in about 60 minutes or less to asize that prevents its passage through the pyloric sphincter.

In certain embodiments, the dosage form of the present disclosuremaintains its integrity in a swollen state for a period of at leastabout 14 hours.

In certain embodiments, the dosage form of the present disclosureprovides comparable bioavailability to marketed extended releasepyridostigmine products, and provides an extended plasma concentrationprofile for up to about 24 hours.

In certain embodiments, the core of the dosage form of the presentdisclosure includes a wicking agent selected from the group consistingof crospovidone; croscarmellose sodium; sodium starch glycolate;low-substituted hydroxypropyl cellulose; a mixture of mannitol,crospovidone, and polyvinyl acetate; a coprocessed blend of mannitol,starch, crospovidone, croscarmellose sodium, colloidal silica, andsilica; microcrystalline cellulose; alginic acid; and mixtures thereof.In certain other embodiments, the core of the dosage form comprisescrospovidone as a wicking agent.

In certain embodiments, the dosage form of the present disclosurecomprises a water-soluble hydrophilic polymer selected from the groupconsisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose,methyl cellulose, a polyethylene oxide polymer, a carbomer, sodiumalginate, and mixtures thereof. In particular embodiments, thewater-soluble hydrophilic polymer is hydroxypropyl methylcellulose. Incertain other embodiments, the water-soluble hydrophilic polymer ismethyl cellulose. In certain other embodiments, the water-solublehydrophilic polymer is a mixture of hydroxypropyl methylcellulose andmethyl cellulose.

In certain embodiments, the dosage form of the present disclosurecomprises a gas-generating agent selected from the group consisting ofNaHCO₃, CaCO₃, and a mixture thereof. In certain embodiments, thegas-generating agent is a mixture of NaHCO₃ and CaCO₃.

In certain embodiments, the dosage form of the present disclosurecomprises a plasticizer is selected from the group consisting oftriethyl citrate, triacetin, polyethylene glycol, propylene glycol,dibutyl sebacate, and mixtures thereof. In particular embodiments, theplasticizer is triethyl citrate.

In certain embodiments, the permeable elastic membrane of the dosageform of the present disclosure is at least partially covered by theimmediate release drug layer.

In certain embodiments, the present disclosure provides for a dosageform that further includes a seal coat between the immediate releasedrug layer and the permeable elastic membrane.

In certain embodiments, the seal coat of the dosage form or the presentdisclosure comprises a water-soluble polymer selected from the groupconsisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, or a mixture thereof.

In certain embodiments, the dosage form of the present disclosurefurther includes an orifice passing through the permeable elasticmembrane and the seal coat.

In certain embodiments, the dosage form of the present disclosurefurther includes an over coat over the immediate release drug layer. Inparticular embodiments, the over coat comprises a water-soluble polymerselected from a group consisting of a polyvinyl alcohol-based polymer,methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, or a mixture thereof.

In certain embodiments, the dosage form of the present disclosure is atablet.

In certain embodiments, the tablet of the present disclosure is suitablefor once daily administration and is administered as a singletablet/day.

In certain embodiments, the present disclosure provides for an extendedrelease gastroretentive pyridostigmine tablet comprising an extendedrelease portion and an immediate release portion, wherein the extendedrelease portion comprises a core comprising pyridostigmine bromide, anacid, a gas-generating agent, and a water-soluble hydrophilic polymerthat swells via imbibition of gastric fluid; and a permeable elasticmembrane, surrounding the core, comprising a plasticizer, and acopolymer based on ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chloride, and the immediate releaseportion comprises an immediate release drug layer containingpyridostigmine bromide, and wherein the tablet is suitable for oncedaily administration and is administered as a single tablet/day.

In certain embodiments, the tablet of the present disclosure providesmembrane-controlled and matrix-controlled extended release, and reducedinitial burst release, of pyridostigmine bromide for at least about 14hours.

In certain embodiments, the tablet of present disclosure comprises 100mg, 200 mg, 250 mg, 300 mg, or 350 mg of pyridostigmine bromide.

In certain embodiments, the water-soluble hydrophilic polymer of thetablet of the present disclosure is selected from the group consistingof hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, a polyethylene oxide polymer, a carbomer, sodium alginate,and mixtures thereof.

In certain embodiments, the gas-generating agent of the tablet of thepresent disclosure comprises NaHCO₃, CaCO₃, or a mixture thereof.

In certain embodiments, the plasticizer of the tablet of the presentdisclosure is selected from the group consisting of triethyl citrate,triacetin, polyethylene glycol, propylene glycol, dibutyl sebacate, andmixtures thereof.

In certain embodiments, the tablet of the present disclosure furtherincludes a wicking agent selected from the group consisting ofcrospovidone; croscarmellose sodium; sodium starch glycolate;low-substituted hydroxypropyl cellulose; a mixture of mannitol,crospovidone, and polyvinyl acetate; a coprocessed blend of mannitol,starch, crospovidone, croscarmellose sodium, colloidal silica, andsilica; microcrystalline cellulose; alginic acid; and mixtures thereof.

In certain embodiments, the permeable elastic membrane of the tablet ofthe present disclosure is at least partially covered by the immediaterelease drug layer.

In certain embodiments, the tablet of the present disclosure furtherincludes a seal coat between the immediate release drug layer and thepermeable elastic membrane.

In certain embodiments, the seal coat of the tablet of the presentdisclosure comprises a water-soluble polymer selected from the groupconsisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, or a mixture thereof.

In certain embodiments, the present disclosure provides for a tabletthat further includes an orifice passing through the permeable elasticmembrane and the seal coat.

In certain embodiments, the present disclosure provides for a tabletthat further includes an over coat over the immediate release druglayer. In certain embodiments, the overcoat of the tablets of thepresent disclosure comprises a water-soluble polymer selected from agroup consisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and mixtures thereof.

In certain embodiments, the present disclosure provides for apyridostigmine bromide pellet comprising an inert core, a drug layercontaining pyridostigmine bromide over the inert core, and a membraneover the drug layer, wherein the membrane comprises a water-insolublelipophilic polymer and a water-soluble hydrophilic polymer, and whereinthe pellet provides extended release, with minimized initial burstrelease, of pyridostigmine bromide, for at least about 14 hours.

In certain embodiments, the water-insoluble lipophilic polymer of thepellet of the present disclosure is selected from the group consistingof an ethyl acrylate and methyl methacrylate copolymer, an ammoniomethacrylate copolymer, ethylcellulose, cellulose acetate, polyvinylacetate, and mixtures thereof.

In certain embodiments, the water-soluble hydrophilic polymer of thepellet of the present disclosure is selected from the group consistingof polyethylene glycol, hydroxypropyl cellulose, hydroxymethylcellulose,carboxymethylcellulose, polyvinyl pyrolidone, methylcellulose, xanthangum, guar gum, sodium alginate, starch, a copolymer of polyvinyl acetateand polyvinyl pyrolidone, a copolymer of ethylene glycol and propyleneglycol, a copolymer of polyvinyl alcohol and polyethylene glycol, andmixtures thereof.

In certain embodiments, the pellet of the present disclosure furthercomprises a seal coat between the drug layer and the membrane.

In certain embodiments, the seal coat of the pellet of the presentdisclosure comprises a water-soluble polymer selected from the groupconsisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and mixtures thereof.

In certain embodiments, the water-soluble polymer of the pellet of thepresent disclosure is hypromellose, hydroxypropyl cellulose, or amixture thereof.

In certain embodiments, the present disclosure provides for atherapeutic method for treating myasthenia gravis, comprising orallyadministering to a subject in need thereof a single QD gastroretentivepyridostigmine bromide tablet, wherein the tablet provides an extendedrelease, with minimized initial burst release, of pyridostigmine bromidefor up to about 24 hours, and wherein the minimized initial burstrelease comprises release of not more than 20% of pyridostigmine bromidewithin two hours of dissolution in a dissolution medium. In certainembodiments, the dissolution medium comprises 50 mM acetate buffer with100 mM NaCl.

In certain embodiments, the present disclosure provides for a method forreducing GI side effects in a patient consuming a pyridostigminecomposition, the method comprising administering to the patient agastroretentive pyridostigmine composition comprising an extendedrelease portion and an immediate release portion as a single tablet/day,wherein the composition provides an extended release, with a reducedinitial burst release, of pyridostigmine bromide for at least about 14hours, and wherein the reduced initial burst release comprises releaseof between 20% and 35% of pyridostigmine bromide within two hours ofdissolution of the composition into a dissolution medium.

In certain embodiments, the present disclosure provides for agastroretentive dosage form comprising pyridostigmine bromide.

In certain other embodiments, the gastroretentive dosage form comprisingpyridostigmine bromide of the present disclosure provides extendedrelease of pyridostigmine bromide for up to 24 hours.

In certain embodiments, the gastroretentive dosage form comprisingpyridostigmine bromide of the present disclosure comprises an immediaterelease portion and an extended release portion, wherein both theextended release portion and the immediate release portion containpyridostigmine bromide, and wherein the dosage form provides an extendedrelease, with reduced initial burst release, of pyridostigmine bromide,for at least about 14 hours.

In certain embodiments, the present disclosure provides for a method forimproving patient compliance in a patient consuming a pyridostigminecomposition, the method comprising administering to the patient agastroretentive pyridostigmine composition comprising an extendedrelease portion and an immediate release portion as a single tablet/day,wherein the composition provides an extended release, with a reducedinitial burst release, of pyridostigmine bromide for at least about 14hours.

In certain embodiments, the present disclosure provide for ahorizontally compressed, oval-shaped gastroretentive tablet dosage formcontaining a long axis and a short axis, wherein the long axis isbetween about 12 mm and about 22 mm long, and the short axis is betweenabout 8 mm and about 11 mm wide, and wherein the tablet, when in contactwith media simulating gastric conditions, floats in about 30 minutes orless, and expands in about 60 minutes or less to a size that preventsits passage through a pyloric sphincter of a human.

5. BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B depict schematic representations of pyridostigminepellets, with and without an immediate release drug layer. FIG. 1Adepicts a schematic representation of a pyridostigmine pellet containinga cellet core, an extended release drug layer, a seal coat and afunctional coat. FIG. 1B depicts a schematic representation of apyridostigmine pellet containing a cellet core, an extended release druglayer, a seal coat, a functional coat, a second seal coat, an immediaterelease drug layer, and an over coat.

FIGS. 2A and 2B depict schematic representations of pyridostigminematrix tablets. FIG. 2A depicts a schematic representation of apyridostigmine matrix tablets containing a matrix core, a functionalcoat and an over coat. FIG. 2B depicts a schematic representation of apyridostigmine matrix tablets containing a matrix core, a functionalcoat, an immediate release drug layer and an over coat.

FIGS. 3A and 3B depict schematic representations of pyridostigminegastroretentive tablets. FIG. 3A depicts schematic representation of apyridostigmine gastroretentive tablet containing a core, a seal coat, afunctional coat and an over coat. FIG. 3A depicts schematicrepresentation of a pyridostigmine gastroretentive tablet containing acore, a seal coat, a functional coat, an immediate release drug layer,and an over coat.

FIG. 4 compares dissolution profiles of pyridostigmine bromide fromTablets 8, 9, and 10, in about 900 ml of pH 4.5 acetate buffer, usingUSP Apparatus I—Custom basket, at about 100 rpm and about 37° C.

FIG. 5 compares dissolution profiles of pyridostigmine bromide fromPellets 2 and 3, in 200 ml of 50 mM phosphate buffer at about pH 6.8,using USP Apparatus II.

FIG. 6 compares dissolution profiles of pyridostigmine bromide fromPellets 9, 10, and 11, in 200 ml of 50 mM phosphate buffer at about pH6.8, using USP Apparatus II.

FIG. 7 compares dissolution profiles of Tablets 8, 13, and 14 in about900 ml of pH 5.0 acetate buffer containing 150 mM NaCl, using USPApparatus I (Custom Basket), at about 100 rpm and about 37° C. FIG. 7shows that Tablets 13 and 14 (containing METHOCEL™ K100 Premium DC andequinormal amounts of succinic acid and gas-generating agents) provideabout 10-15% slower drug release compared to Tablet 8 (containingBENECEL™ K4M PH DC and nonequinormal amounts of succinic acid andgas-generating agents).

FIG. 8 compares dissolution profiles of Tablets 13 and 14, each with andwithout an orifice/hole in the membrane/functional coat, and Tablet 8(with an orifice). The dissolution testing was conducted in about 250 mlof pH 3.0 media containing about 100 mM NaCl, using USP Apparatus III(BIO-DIS), at about 25 dpm and about 37° C.

FIG. 9 compares dissolution profiles of Tablets 8, 14, and 14A, thelatter two with (“H”) and without a hole in the membrane. Thedissolution testing was conducted in about 900 ml of pH 5.0 acetatebuffer containing about 150 mM NaCl, using USP Apparatus I (CustomBasket), at about 100 rpm and about 37° C.

FIG. 10 compares floating lag times of Tablets 8, 11, 13, and 15, with(“H”) and without a hole, at 200 mg functional coating weight gain, andTablets 8A, 11A, 13A, and 15A, with and without a hole, at 250 mgfunctional coating weight gain. The flotation studies were performedusing a Rotating Bottle method at about 5 rpm and about 37° C., in 200ml of a dissolution medium at about pH 4.5 comprising about 100 mM NaCl.

FIG. 11 compares volumetric expansion at flotation of Tablets 8, 11, 13,and 15, with (“H”) and without a hole, at 200 mg functional coatingweight gain, and Tablets 8A, 11A, 13A, and 15A, with and without a hole,at 250 mg functional coating weight gain. FIG. 11 demonstrates thattablets without a hole exhibit higher volume expansion compared totablets with a hole at flotation. The volume expansion studies wereperformed, using a Rotating Bottle method at about 5 rpm and about 37°C., in 200 ml of pH 4.5 dissolution medium containing about 100 mM NaCl.

FIG. 12 compare volumetric expansion, at 90 minutes and one hour, ofTablets 8, 11, 13, and 15, with (“H”) and without a hole, at 200 mgfunctional coating weight gain, and Tablets 8A, 11A, 13A, and 15A, withand without a hole, at 250 mg functional coating weight gain. FIG. 12demonstrates that tablets without a hole exhibit higher volume expansioncompared to tablets with a hole at both 90 minutes and one hour. Thevolume expansion studies were performed, using a Rotating Bottle methodat about 5 rpm and about 37° C., in 200 ml of pH 4.5 dissolution mediumcontaining about 100 mM NaCl.

FIG. 13 compares volumetric expansion and weight gain at 24 hours ofTablets 8, 11, 13, and 15, with (“H”) and without a hole, at 200 mgfunctional coating weight gain. The volume expansion studies wereperformed, using a Rotating Bottle method at about 5 rpm and about 37°C., in 200 ml of pH 4.5 dissolution medium containing about 100 mM NaCl.FIG. 13 demonstrates that tablets containing 200 mg of crospovidone(e.g., Tablets 11/11-H and 15/15-H) exhibit higher weight upon dryingcompared with tablets containing 100 mg of crospovidone (e.g., Tablets8/8-H and 13/13-H).

FIG. 14 compares dissolution profiles of Tablets 8B, 15, 16, and 17without a hole, and Tablets 8, 8B, 15, 16, and 17 with a hole (“H”),using BIO-DIS method at about 20 dpm and about 37° C., in 250 ml of pH3.0 dissolution medium containing about 100 mM NaCl. FIG. 14demonstrates that tablets without a hole exhibit slower drug releaserates compared to tablets with a hole.

FIG. 15 shows the effect of crospovidone on release rates ofpyridostigmine from the gastroretentive compositions of the disclosure.FIG. 15 compares dissolution profiles of Tablets 8, 18, and 19 in about900 ml of pH 5.0 dissolution medium containing about 150 mM NaCl, 30 mMsodium acetate, and 17 mM acetic acid, using USP Apparatus I (CustomBasket), at about 100 rpm and about 37° C. FIG. 15 demonstrates thattablets containing 200 mg of crospovidone (Tablets 18 and 19) exhibitfaster drug release compared to a tablet containing 100 mg ofcrospovidone (Tablet 8).

FIG. 16 compares dissolution profiles of tablets containing a mixture ofBENECEL K4M PH DC and METHOCEL K100 Premium DC (Tablets 20 and 21) and atablet containing BENECEL K4M PH DC only (Tablet 8) in about 900 ml ofpH 5.0 buffer containing about 150 mM NaCl, using USP Apparatus I(Custom Basket), at about 100 rpm and about 37° C. FIG. 16 demonstratesthat tablets containing the mixture (Tablets 20 and 21) provide morecontrolled release compared to a tablet containing BENECEL™ K4M PH DConly (Tablet 8).

FIG. 17 compares dissolution profiles of tablets (all with a hole (“H”))containing an immediate release drug layer (Tablet 23) and tablets withno immediate release drug layer (Tablets 8 and 22) in about 900 ml of pH5.0 buffer containing about 150 mM NaCl, using USP Apparatus I (CustomBasket), at about 100 rpm and about 37° C. FIG. 17 demonstrates that thetablet containing an immediate release drug layer (Tablet 23) eliminateslag time compared to those that do not contain an immediate release druglayer (Tablets 8 and 22).

FIG. 18 compares pharmacokinetic data for gastroretentive Tablet 8 (T₁),pellet composition (T₂), and marketed pyridostigmine products, e.g.,MESTINON® tablets (R₂) and ER MESTINON® (i.e., TIMESPAN®) tablets (R₁).

FIG. 19 provides schematic and photographic representations of thegastroretentive dosage form of the disclosure from its initial tabletform to its residue after drug release.

FIG. 20 compares pharmacokinetic data for gastroretentive Tablet 34,with a hole in the functional coat, under low fat-low calorie (LF-LC)breakfast conditions (Condition I) and high fat-high calorie (HF-HC)breakfast conditions (Condition II). FIG. 20 demonstrates that Tablet 34provides a therapeutic plasma concentration of pyridostigmine for atleast about 22 hours.

FIG. 21 compares pharmacokinetic data for gastroretentive Tablet 35,without a hole in functional coat, under LF-LC breakfast conditions(Condition I) and HF-HC breakfast conditions (Condition II). FIG. 21demonstrates that Tablet 35 provides a therapeutic plasma concentrationof pyridostigmine for at least about 22 hours.

FIG. 22 provides a steady state plasma concentration of pyridostigminebromide from Tablet 34, day 5, based on a steady state simulation forTablet 34 over a 5-day period. FIG. 22 demonstrates that Tablet 34 canprovide and maintain therapeutic plasma concentrations ofpyridostigmine, e.g., about 20 ng/ml, for a period of at least about 14hours.

FIG. 23 compares in vitro dissolution profiles of a tablet containing animmediate release drug layer (Tablet 34), tablet with no immediaterelease drug layer (Tablet 8), and MESTINON® TIMESPAN, in 50 mM acetatebuffer with 100 mM NaCl. FIG. 23 demonstrates that Tablet 34 exhibits asubstantial decrease in (e.g., elimination of) lag time compared toTablet 8. FIG. 23 further demonstrates that Tablet 8 (without IR druglayer) exhibits minimized initial burst release; and Tablet 34 (with IRdrug layer) provides an immediate release of a therapeutic amount ofpyridostigmine bromide, with reduced initial burst release (less thanabout 35% drug release in about 2 hours) of the drug, compared toMESTINON® TIMESPAN.

FIG. 24 compares pharmacokinetic data for gastroretentive Tablet 34,with a hole in the functional coat, under LF-LC breakfast conditions(Condition I) and HF-HC breakfast conditions (Condition II), andMESTINON® TIMESPAN, under HF-HC breakfast conditions (Condition II).FIG. 24 demonstrates that MESTINON® TIMESPAN provides higher drug plasmaconcentrations between about 0 and 5 hours compared to Tablet 34 underConditions I and II. FIG. 24 further demonstrates that Tablet 34, underConditions I and II, provides higher drug plasma concentrations over anextended time period, e.g., about 7 hours or beyond, compared toMESTINON® TIMESPAN.

6. DETAILED DESCRIPTION

The presently disclosed subject matter provides extended releasepyridostigmine compositions suitable for once-daily administration. Incertain embodiments, the composition is suitable for twice-dailyadministration. In certain embodiments, the compositions of thedisclosure provide dual-controlled release, e.g., membrane-controlledand matrix-controlled extended release, of pyridostigmine bromide. Suchdual-controlled release results in maintaining therapeutic plasmaconcentration, with minimized dose dumping (minimized initial burstrelease) of pyridostigmine bromide, and overcome the gastrointestinalside effects associated with the currently marketed extended releasepyridostigmine products. In certain embodiments, the lag time associatedwith the extended release compositions of the disclosure is eliminatedwith the presence of an immediate release portion. In certainembodiments, the extended release compositions containing an IR druglayer substantially reduce or eliminate dose dumping of the drugcompared to marketed extended release pyridostigmine products. Theextended release pyridostigmine compositions of the disclosure can beformulated as gastroretentive tablets, matrix tablets, and pelletssuitable for dosing in capsules, tablets, sachets, and as sprinkledpellets on food. In certain embodiments, the pyridostigmine compositionscan be formulated as gastroretentive tablets providing extended releaseof pyridostigmine bromide. In certain embodiments, the compositions ofthe disclosure provide extended release of pyridostigmine bromide for atleast about 14 hours, e.g., about 18 hours, about 24 hours. In certainembodiments, the disclosure provides methods for making matrix tablets,pellets, and gastroretentive tablets comprising pyridostigmine bromide.

For clarity and not by way of limitation, this detailed description isdivided into the following sections:

6.1. Definitions;

6.2. Pyridostigmine Dosage Forms;

6.3. Methods of Making; and

6.4. Methods of Treatment.

6.1. Definitions

The terminology used in the present disclosure is for the purpose ofdescribing particular embodiments only and is not intended to belimiting. As used herein, the use of the word “a” or “an” when used inconjunction with the term “comprising” in the claims and/or thespecification can mean “one,” but it is also consistent with the meaningof “one or more,” “at least one,” and “one or more than one.” Stillfurther, the terms “having,” “including,” “containing,” and “comprising”are interchangeable, and one of skill in the art is cognizant that theseterms are open-ended terms.

As used herein, “and/or” refers to and encompasses any and all possiblecombinations of one or more of the associated listed items. The term“about” or “approximately” means within an acceptable error range forthe particular value as determined by one of ordinary skill in the art,which will depend in part on how the value is measured or determined,i.e., the limitations of the measurement system. For example, “about”can mean within 3 or more than 3 standard deviations, per the practicein the art. Alternatively, “about” can mean a range of up to 20%, up to15%, up to 10%, up to 5%, up to 1%, up to 0.5%, or even up to 0.1% of agiven value. Unless otherwise defined, all terms, including technicaland scientific terms used in the description, have the same meaning ascommonly understood by one of ordinary skill in the art to which thepresent disclosure belongs. As used herein, “about” will be understoodby persons of ordinary skill in the art and will vary to some extent onthe context in which it is used. If there are uses of the term which arenot clear to person of ordinary skill in the art given the context inwhich it is used, “about” will mean up to about ±10% of the particularterm.

As used herein, a “therapeutically effective” or “therapeuticallyacceptable” amount refers to an amount that will elicit atherapeutically useful response in a subject and includes an additionalamount or overage of active ingredient deemed necessary in theformulation to provide the desired amount upon administration. Thetherapeutically useful response can provide some alleviation,mitigation, and/or decrease in at least one clinical symptom in thesubject. Those skilled in the art will appreciate that thetherapeutically useful response need not be complete or curative, aslong as some benefit is provided to the subject. In some embodiments,the subject is a human.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, and/or inhibiting theprogress of a disease or disorder as described herein. In someembodiments, treatment can be administered after one or more symptomshave developed. In other embodiments, treatment can be administered inthe absence of symptoms. For example, treatment can be administered to asusceptible individual prior to the onset of symptoms (e.g., in light ofa history of symptoms and/or in light of genetic or other susceptibilityfactors). Treatment can also be continued after symptoms have resolved,for example to prevent or delay their recurrence.

As used herein, the term “immediate release” refers to release of atleast 70% of a drug in one hour (i.e., one hour post-administration).

As used herein, the terms “extended release” and “sustained release” canbe used interchangeably and refer to dosage forms or compositions thatare formulated to provide therapeutic drug concentrations over anextended period of time after administration, thereby allowing areduction in dosing frequency, as compared to a drug presented as animmediate release dosage form.

As used herein, the term “extended release coating” refers to a coatingproviding extended release properties, e.g., a coating which slows therelease of the drug from the dosage form.

As used herein, the term “floating” is used in conjunction with a“floating gastroretentive dosage form”, which has a bulk density lessthan gastric fluids. Such dosage forms are “floating” in that theyremain buoyant in the gastric fluids of the stomach for a targetedperiod of time. The floating dosage form then is able to be retained inthe stomach, while releasing an active agent.

As used herein, the term “floating lag time,” refers to the time betweenthe addition of a dosage form to a medium and the time when the dosageform begins to float on the medium (e.g., in an in vitro setting), orthe time between the consumption of a dosage form by a user and the timewhen the dosage form begins to float on the surface of the gastric fluid(e.g., in an in vivo setting).

As used herein, the term “gastroretentive dosage form,” can be usedinterchangeably with the term “gastroretentive oral floating drugdelivery system”. These terms refer to modified release dosage formsproviding delayed gastric emptying as compared to food (e.g., retentionin the stomach beyond the retention of food).

The term “pyridostigmine,” as used herein, refers to the pyridostigmineas well as all pharmaceutically acceptable salts, esters, andfunctionally equivalent chemical compounds of pyridostigmine.

The terms “initial burst release” and/or “dose dumping”, as use herein,refer to an unintended initial spike in concentration of pyridostigminein extended release dosage forms.

The terms “reduced initial burst release”, and the like, as used herein,refer to in vitro release of from about 20% to about 35% of thepyridostigmine within two hours of dissolution into a dissolution mediumcomprising 50 mM acetate buffer with 100 mM NaCl.

The terms “minimized initial burst release”, and the like, as usedherein, refer to in vitro release of not more than 20% of thepyridostigmine within two hours of dissolution into a dissolution mediumcomprising 50 mM acetate buffer with 100 mM NaCl.

The terms “pore former” and the like, as used herein, refer towater-soluble polymers and/or water-soluble small molecules that willform pores or channels (i.e., behave as a channeling agent) in thefunctional coat, thereby creating a permeable functional coat/membrane.The term “pore former” includes molecules used to create a certainamount of diffusion through an insoluble (or sparingly soluble) coatingof a tablet, pellet, or particle to achieve an extended release profile.

The term “simulated gastric fluid,” as used herein, refers to mediumthat is used to mimic the chemical environment of gastric medium invitro.

The term “gastric fluid,” as used herein, refers to medium occurring instomach of an individual.

The term “dissolution media,” as used herein, refers to biorelevantmedia mimicking gastric fluid conditions. In certain embodiments, themedia includes 50 mM of pH 4.5 acetate buffer; 50 mM of pH 4.5 bufferwith 100 mM NaCl; pH 5.0 buffer with 150 mM NaCl; and pH 2.0 medium with0.01 N HCl.

The terms “swellable,” “swelling,” and the like, as used herein withrespect to a polymer, refer to a polymer capable of imbibing fluid andswelling when in contact with a fluid environment.

The terms “expanding,” “expansion,” and the like, as used herein withrespect to a permeable elastic membrane, refer to stretching ordistention of a membrane due to the presence of at least oneplasticizer, and an outward pressure, e.g., gas pressure, on themembrane.

The term “permeable,” as used herein, refers to a membrane containingsparingly soluble polymers, or insoluble polymers, with or without apore former, that will allow particles and fluids to pass throughmembrane by diffusion. As used herein, the terms functional coat andpermeable membrane are used interchangeably.

The terms “wicking agent,” and “disintegrants,” as used interchangeablyherein, refer to a material(s) with the ability to draw and spread waterinto the porous core of the dosage form. Wicking agents help to increasethe contact surface area of the drug with the incoming aqueous fluid,which helps to enhance the rate of drug released from the dosage form.Wicking agents carry water to surfaces inside the core of the tablet tocreate channels or a network of increased surface area.

The term “dual-controlled release,” as used herein, refers to drugrelease from a membrane-controlled matrix (also referred to as amembrane-controlled matrix core or membrane-controlled core). The term“dual-controlled release” includes drug release that is controlled byboth the matrix and the membrane portions of the dosage form, e.g.,matrix-controlled and membrane-controlled release of pyridostigminebromide.

6.2. Pyridostigmine Dosage Forms

The disclosed subject matter provides for extended release compositionscontaining pyridostigmine. The presently disclosed subject matter alsoprovides for formulating the extended release compositions containingpyridostigmine into various dosage forms, such as, e.g., matrix tablets,gastroretentive tablets, and pellets. In certain embodiments, thepresent disclosure provides for dosage forms that contain an IR portionto eliminate the lag time. In certain embodiments, the dosage formsprovide reduced initial drug concentration, compared to marketedextended release pyridostigmine products. In certain embodiments, theextended release dosage forms of the present disclosure are formulatedto minimize the “dose dumping” drug release (also referred to herein as“minimized initial burst release”) during the first one to two hours ofdissolution, compared with the currently marketed ER pyridostigmineproducts. Such dose dumping is believed to be responsible for unwantedGI side effects experienced with the currently marketed ERpyridostigmine products. Thus, the extended release dosage forms of thedisclosure minimize the GI side effects, and provide and maintaintherapeutic plasma concentrations of pyridostigmine for a period of atleast about 14 hours. In certain embodiments, the extended releasepyridostigmine dosage forms of the disclosure provide residual plasmalevels of the drug in the morning, such that patients wake up feelingmore refreshed and more functional before taking the morning dose, ascompared with the currently marketed pyridostigmine products. In certainembodiments, the reduced initial drug concentration (e.g., reducedinitial burst release) is sufficient to provide a therapeutic effect andavoid GI side effects. In certain embodiments, the extended releasedosage forms of the disclosure are administered with an IRpyridostigmine dosage form to eliminate the lag time.

In certain embodiments, the gastroretentive dosage form comprisingpyridostigmine bromide of the present disclosure provides extendedrelease of pyridostigmine bromide for up to 24 hours.

In certain embodiments, the gastroretentive dosage form comprisingpyridostigmine bromide of the present disclosure comprises an immediaterelease portion and an extended release portion, wherein both theextended release portion and the immediate release portion containpyridostigmine bromide, and wherein the dosage form provides an extendedrelease, with reduced initial burst release, of pyridostigmine bromide,for at least about 14 hours.

The extended release compositions described herein comprisepyridostigmine and/or pharmaceutically acceptable salts thereof.Nonlimiting pharmaceutically acceptable salts include hydrochloride,hydrobromide, hydroiodide, bromide, sulfite, sulfate, bisulfate,nitrate, salicylate, citrate, tartrate, bitartrate, lactate, phosphate,malate, maleate, fumarate, succinate, acetate, and pamoate salts. Incertain embodiments, the pharmaceutically acceptable salt is bromide.

In certain embodiments, pyridostigmine is present in amounts of fromabout 50 mg to about 400 mg per dose, and any other range in between. Incertain embodiments, pyridostigmine can be present in amounts from about60 mg to about 400 mg, from about 60 mg to about 360 mg, from about 60mg to about 300 mg, from about 60 mg to about 240 mg, from about 60 mgto about 180 mg, or from about 60 mg to about 120 mg per dose, and anyother range in between. In certain embodiments, pyridostigmine can bepresent in an amount of about 100 mg, about 200 mg, about 250 mg, about300 mg, about 350 mg, or about 400 mg per dose to provide a wide rangeof doses depending on the disease severity. In certain embodiments, thepyridostigmine is present in an immediate release portion and anextended release portion. In certain embodiments, the compositions ofthe disclosure include the following dose-similar amounts of IR and ERportions: about 30 mg/about 70 mg; about 45 mg/about 155 mg; about 45mg/about 205 mg; about 45 mg/about 255 mg; about 45 mg/about 305 mg; orabout 45 mg/about 355 mg. In certain embodiments, the compositions ofthe disclosure include the following dose-proportional amounts of IR andER portions: about 10 mg/about 50 mg; about 15 mg/about 85 mg; about 30mg/about 70 mg; about 37.5 mg/about 212.5 mg; or about 52.5 mg/about297.5 mg. In certain embodiments, the compositions of the disclosure canbe administered QD as a single dosage unit. In certain embodiments, thecompositions of the disclosure can be administered QD as multiple dosageunits (e.g., two, three, or four dosage units).

In certain embodiments, the present disclosure provide for ahorizontally compressed, oval-shaped gastroretentive tablet dosage formcontaining a long axis and a short axis, wherein the long axis isbetween about 12 mm and about 22 mm long, and the short axis is betweenabout 8 mm and about 11 mm wide, and wherein the tablet, when in contactwith media simulating gastric conditions, floats in about 30 minutes orless, and expands in about 60 minutes or less to a size that preventsits passage through a pyloric sphincter of a human.

6.2.1. Matrix Tablets

In certain embodiments, the extended release pyridostigmine compositionsof the disclosure can be formulated as a matrix tablet comprising a ratecontrolling matrix core coated with a rate controlling functionalcoat/membrane, e.g., membrane-controlled matrix.

In certain embodiments, the matrix tablet of the disclosure can comprisea rate-controlling matrix core coated with a rate-controlling functionalcoat/membrane, e.g., a membrane-controlled matrix core. In certainembodiments, the matrix tablet of the disclosure can comprise arate-controlling matrix core, a seal coat over the matrix core, afunctional coat/membrane over the seal coat, an over coat over thefunctional coat, an immediate release layer over the over coat, and anaesthetic coat over the immediate release layer. In certain embodiments,the matrix tablet can exclude an immediate release layer. In particularembodiments, in the absence of an immediate release layer, the over coatis the outermost coat.

In certain embodiments, the matrix core can be made by dry granulation.In certain embodiments, the matrix core can comprise pyridostigminebromide, and at least one water-insoluble pH-independent lipophilicmaterial. In certain embodiments, the matrix tablets can comprisepyridostigmine bromide and at least one swellable water-solublehydrophilic polymer. As matrix tablets can be susceptible to stickingand mottling due to the hygroscopic nature of pyridostigmine bromide,the matrix tablets of the present disclosure can include an over coat toreduce the exposure of pyridostigmine bromide to moisture. In certainembodiments, the over coat can be the outermost coat. In certainembodiments, the release rate of pyridostigmine bromide from the matrixtablets of the disclosure can be controlled by varying the amount oflipophilic material in the matrix core and the composition of thefunctional coat over the matrix core. In certain embodiments, therelease rate of pyridostigmine bromide from the compositions of thedisclosure can be controlled by adjusting the coating level of thefunctional coat over the matrix core. In certain embodiments,water-insoluble lipophilic material in the matrix core reduces drugdissolution and provides extended release of the drug, without initialburst release, for extended periods of time. In certain embodiments, thewater-insoluble lipophilic material can enhance compressibility of thecomposition. In certain embodiments, the water-insoluble lipophilicmaterial can include, but is not limited to, ethyl acrylate and methylmethacrylate copolymer (EUDRAGIT® NE, EUDRAGIT® NM), ammoniomethacrylate copolymer (EUDRAGIT® RL, EUDRAGIT® RS, EUDRAGIT® RL PO,EUDRAGIT® RS PO), carnauba wax, stearic acid, ethylcellulose (ETHOCEL™),cellulose acetate, and silicon dioxide.

In certain embodiments, the matrix core can further comprise glidants,lubricants, compression aids, and fillers.

In certain embodiments, the disclosed matrix tablets can comprise one ormore glidant materials to improve the flow of granules, and help tominimize the dosage form from weight variations. In certain embodiments,the glidants include, but are not limited to, silicon dioxide (SYLOID®244FP), fumed silica (CAB-O-SIL®), talc, kaolin, or any combinationsthereof.

In certain embodiments, the disclosed matrix tablets can comprisediluents and/or fillers. In certain embodiments, the diluents and/orfillers include, but are not limited to, lactose monohydrate USP,anhydrous lactose USP, directly compressible starches, hydrolyzedstarches, pregelatinized starch, microcrystalline cellulose, silicifiedmicrocrystalline cellulose, carboxymethylcellulose and other cellulosepolymers, sucrose and sucrose-based materials, dextrose, dibasic calciumphosphate anhydrous, dibasic calcium phosphate dihydrate, tricalciumphosphate, calcium sulfate dihydrate, and other alkaline inorganicsalts, sugar alcohols such as mannitol (e.g., PARTECK® M200, MANNOGEM®XL), sorbitol, and xylitol, and confectioner's sugar.

In certain embodiments, diluents and/or fillers can be used ascompression aids. In certain embodiments, diluents and/or fillers thatcan be used as compression aids include, but are not limited to,microcrystalline cellulose, silicified microcrystalline cellulose, andmannitol (e.g., PARTECK® M200). In certain embodiments, the diluentand/or filler can be used in an amount of less than about 30% w/w of thetablet core. In certain embodiments, the diluent and/or filler can bepresent in an amount of from about 10% to about 40% w/w of the tablet.In certain embodiments, the diluent and/or filler can be present in anamount of less than about 25% w/w, less than about 24% w/w, less thanabout 23% w/w, less than about 22% w/w, less than about 21% w/w, lessthan about 20% w/w, less than about 15% w/w, less than about 10% w/w,less than about 5% w/w, or less than about 2.5% w/w of the total weightof the tablet core, or intermediate values thereof.

In certain embodiments, the matrix core can also include one or morelubricants. Lubricants are hydrophobic substances that decrease frictionat the interface between a tablet's surface and the die wall duringejection and reduce wear on punches and dies. Lubricants enhance productflow by reducing interparticulate friction. In certain embodiments, theone or more lubricants can be, but are not limited to, magnesiumstearate, stearic acid, calcium soaps, zinc stearate, polyoxyethylenemonostearate, solid polyethylene glycols, calcium silicate, colloidalsilicon dioxide, hydrogenated vegetable oils and fats, glycerylmonostearate, palmitic acid, talc, carnauba wax, mineral oil,polyethylene glycol, glyceryl palmitostearate, sodium benzoate, sodiumstearyl fumarate, and any combination thereof. In certain embodiments,the lubricant is magnesium stearate. In certain embodiments, thelubricant can be present in an amount of from about 0.1% w/w to about 5%w/w based on the total weight of the matrix core. In certainembodiments, the lubricant can be present in an amount of less thanabout 4% w/w, less than about 3% w/w, less than about 2% w/w, less thanabout 1.5% w/w, less than about 1.4% w/w, less than about 1.3% w/w, lessthan about 1.2% w/w, less than about 1.1% w/w, or less than about 1.0%w/w based on the total weight of the matrix core.

In certain embodiments, the drug release can be controlled by amatrix-controlled membrane, e.g., a matrix core and functional coat overthe matrix core. In certain embodiments, the drug release can becontrolled by the functional coat/membrane. In certain embodiments, thematrix core can contain rate controlling hydrophobic material selectedfrom a group comprising, but not limited to, ethyl acrylate and methylmethacrylate copolymer (EUDRAGIT® NE, EUDRAGIT® NM), ammoniomethacrylate copolymer (EUDRAGIT® RL, EUDRAGIT® RS), carnauba wax,stearic acid, ethylcellulose (ETHOCEL™), cellulose acetate, and silicondioxide. In certain embodiments, the matrix core can containrate-controlling swellable water-soluble hydrophilic polymer selectedfrom the group comprising, but not limited to, hydroxypropylmethylcellulose (BENECEL™ K4M PH DC), hydroxypropyl methylcellulose(METHOCEL K100 Premium LVCR), a polyethylene oxide polymer, a carbomer,sodium alginate, or mixtures thereof. In certain embodiments, theswellable water-soluble hydrophilic polymer can be BENECEL™ K4M PH DC.In certain embodiments, the water-soluble hydrophilic polymer can beMETHOCEL K100 Premium LVCR. In certain embodiments, the water-solublehydrophilic polymer can be a mixture of METHOCEL K100 Premium LVCR andBENECEL™ K4M PH DC.

In certain embodiments, the functional coat can contain rate controllinghydrophobic material. In certain embodiments, the rate controllingpolymers in the functional coat can comprise, but are not limited to,ethyl acrylate and methyl methacrylate copolymer (EUDRAGIT® NE,EUDRAGIT® NM), ammonio methacrylate copolymer (EUDRAGIT® RL, EUDRAGIT®RS, EUDRAGIT® RL PO, EUDRAGIT® RS PO), carnauba wax, stearic acid,ethylcellulose (ETHOCEL™), cellulose acetate, and polyvinyl acetatedispersion (KOLLICOAT® SR). In certain embodiments, the functional coatcan further comprise a water-soluble pore former. In certainembodiments, the water-soluble pore former can include, but is notlimited to, polyethylene glycol (PEG 400, PEG 1000, PEG 1450, PEG 3350),hydroxypropyl cellulose, polyvinyl pyrolidone (PVP), KOLLIDON® 30,KOLLICOAT® IR, mannitol, and methylcellulose (METHOCEL™ E3, METHOCEL™E5, METHOCEL™ E6).

In certain embodiments, the matrix core and the functional coat over thematrix core can include stearic acid, ethylcellulose, cellulose acetate,and/or silicon dioxide to control the release of pyridostigmine bromide.In certain embodiments, the matrix core can be at least partiallycovered with the functional coat. In certain embodiments, the functionalcoat can completely surround the matrix core.

In certain embodiments, the matrix tablet can further include a sealcoat between the matrix core and the functional coat. In certainembodiments, the seal coat can cover at least a portion of the matrixcore. In certain embodiments, the seal coat can comprise a nonionicwater-soluble polymer. In certain embodiments, the nonionicwater-soluble polymer can be selected from the group consisting of apolyvinyl alcohol-based polymer, methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, andmixtures thereof.

In certain embodiments, the matrix tablet can further include an overcoat. In certain embodiments, the over coat can cover at least a portionof the functional coat. In certain embodiments, the over coat cancompletely cover the functional coat. In certain embodiments, the overcoat can comprise one or more water-soluble hydrophilic polymersselected from the group consisting of water-soluble polymer selectedfrom a group consisting of a polyvinyl alcohol-based polymer (e.g.,Opadry®II), methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and mixtures thereof. Incertain embodiments, the water-soluble hydrophilic polymers in the overcoat can include polyvinyl alcohol and polyethylene glycol, e.g.,Opadry® White.

In certain embodiments, the over coat can be further coated with animmediate release layer comprising pyridostigmine. In certainembodiments the immediate release layer comprises pyridostigminebromide. In certain embodiments, the immediate release layer can befurther coated with an aesthetic coat.

In certain embodiments, the matrix tablets can comprise a matrix coreand a functional coat. In certain embodiments, the matrix core cancomprise one or more of pyridostigmine bromide, stearic acid, carnaubawax, ethylcellulose, silicon dioxide, fumed silica, mannitol, magnesiumstearate and combinations thereof. In certain embodiments, the matrixcore can comprise from about 100 mg to about 250 mg, from about 150 mgto about 200 mg, or about 180 mg of pyridostigmine bromide. In certainembodiments, the matrix core can further optionally comprise from about20 mg to about 200 mg, from about 50 mg to about 180, or about 90 mg ofstearic acid. In certain embodiments, the matrix core can furtheroptionally comprise from about 50 mg to about 200 mg, or from about 80mg to about 160 mg of carnauba wax. In certain embodiments, the matrixcore can further optionally comprise from about 50 mg to about 150 mg,or about 100 mg of ethylcellulose. In certain embodiments, the matrixcore can further optionally comprise from about 20 mg to about 250 mg,from about from about 50 mg to about 200 mg, or about 180 mg of silicondioxide. In certain embodiments, the matrix core can further optionallycomprise from about 5 mg to about 40 mg, from about 10 mg to about 25mg, or about 20 mg of fumed silica. In certain embodiments, the matrixcore can further comprise from about 50 mg to about 200 mg, from about75 mg to about 150 mg, or about 100 mg of mannitol. In certainembodiments, the matrix core can further comprise from about 1 mg toabout 10 mg, from about 3 mg to about 7 mg, or about 5 mg of magnesiumstearate. In certain embodiments, the matrix tablet comprises afunctional coat. In certain embodiments, the functional coat cancomprise one or more of cellulose acetate, polyethylene glycol,methylcellulose, and combinations thereof. In certain embodiments, thefunctional coat can comprise from about 10 mg to about 70 mg, from about30 mg to about 65 mg, or from about 40 mg to about 50 mg of celluloseacetate. In certain embodiments, the functional coat can furthercomprise from about 1 mg to about 10 mg, from about 1.5 mg to about 7mg, or from about 2 mg to about 5 mg of polyethylene glycol. In certainembodiments, the functional coat can further comprise from about 2 mg toabout 10 mg, from about 3 mg to about 7 mg, or from about 3 mg to about5 mg of methylcellulose.

6.2.2. Gastroretentive Tablets

In certain embodiments, the extended release pyridostigmine compositionscan be formulated as gastroretentive tablets that provide a constantreservoir for continuous absorption of pyridostigmine in the proximalgastrointestinal tract and provide constant levels of pyridostigmineover extended periods of time. The sustained release profile with fewerfluctuations in the plasma concentration is expected to fulfill an unmetneed by reducing the frequency of dosing while providing better controlof symptoms and improved tolerability (e.g., decreased side effects,including unwanted GI side effects) compared to currently marketedpyridostigmine products. The gastroretentive compositions (e.g.,tablets) of the disclosure are particularly suitable for long-termtreatment of mild to moderate MG, and as an adjunct therapy in patientswho are also receiving steroids and immunotherapy. In certainembodiments, the gastroretentive tablets of the disclosure can providegastric retention and continuous release of pyridostigmine, withoutinitial dose dumping of pyridostigmine, for at least about 14 hours,e.g., about 24 hours.

In certain embodiments, the gastroretentive tablets of the disclosurecan comprise an expanding core and a permeable elastic membranesurrounding the core, wherein the core and the membrane together canprovide controlled extended release, with minimized (e.g., eliminated)or reduced dose dumping/initial burst release, of pyridostigmine bromidefor at least about 14 hours.

In certain embodiments, the gastroretentive tablets of the disclosurecan comprise an immediate release portion and an extended releaseportion. The immediate release portion can comprise an immediate releasedrug layer containing pyridostigmine bromide, and the extended releaseportion can comprise a core coated with a permeable elastic membrane. Incertain embodiments, the immediate release portion can provide a drugplasma concentration that is sufficient to overcome the lag time inpyridostigmine release seen without application of an IR portion, andsufficient to provide instant therapeutic effects, with reduced oreliminated GI side effects, and the extended release portion can providecontrolled extended release of the drug for a period of at least about14 hours.

In certain embodiments, the gastroretentive tablets of the disclosure,when in contact with simulated gastric medium, can expand in about 60minutes or less to a size that would prevent its passage through apyloric sphincter. In certain embodiments, the gastroretentive tabletsof the disclosure can float in about 10 minutes or less, expand in about60 minutes or less to a size that prevents passage through the pyloricsphincter, and provide extended release of pyridostigmine for at leastabout 14 hours, e.g., about 24 hours.

6.2.2.1 Permeable Membrane/Functional Coat

The gastroretentive compositions (e.g., tablets) of the disclosure caninclude a rapidly expanding membrane surrounding a hydrophilic core. Incertain embodiments, the membrane can be a water-insoluble, permeableelastic membrane surrounding the core. The permeable membrane can allowthe flow of gastric fluid into the composition, which initiates gasgeneration from gas-generating agents, and the membrane flexibility canallow for rapid expansion and immediate flotation of the composition. Incertain embodiments, the membrane can comprise a plasticizer and atleast one ammonium polymethacrylate copolymer.

The ammonium polymethacrylate copolymer can improve permeability of themembrane and the plasticizer can improve elasticity and mechanicalstrength of the membrane. The plasticizer can provide elasticity to themembrane, ensuring that the membrane does not rupture upon expanding andthat the gastroretentive drug delivery system provides the desiredcharacteristics for drug release, hydrodynamic balance, and mechanicalstrength to withstand variations in pH and shear in the stomach duringfed and fasted conditions. In certain embodiments, as dissolution of theactive agent in the core proceeds, the plasticizer can leach out of themembrane. In certain embodiments, leaching of the plasticizer can makethe membrane brittle, such that the membrane does not remain intact andthe dosage form can break into pieces by the end of drug release.Hydrophilic plasticizers suitable for the disclosure include, but arenot limited to, glycerin, polyethylene glycols, polyethylene glycolmonomethyl ether, propylene glycol, sorbitol sorbitan solution, andmixtures thereof. Hydrophobic plasticizers suitable for the disclosureinclude, but are not limited to, acetyl tributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglycerides, dibutylsebacate, diethyl phthalate, triacetin, tributyl citrate, triethylcitrate, gelucire 39/01, gelucire 43/01, and mixtures thereof. Incertain embodiments, the plasticizers include various polyethyleneglycols, glycerin, and/or triethyl citrate. In certain embodiments, theplasticizer is triethyl citrate.

In certain embodiments of the disclosure, the permeable elastic membranecan comprise two (or more) water-insoluble polymers: at least one ofEUDRAGIT® RL 30D (copolymer dispersion of ethyl acrylate, methylmethacrylate, and methacrylic acid ester with quaternary ammoniumgroups, 1:1:0.1) and EUDRAGIT® RS 30D (copolymer dispersion of ethylacrylate, methyl methacrylate, and methacrylic acid ester withquaternary ammonium groups, 1:2:0.1) to improve permeability; and atleast one of KOLLICOAT® SR 30D (dispersion of polyvinyl acetate andpolyvinyl pyrolidone), EUDRAGIT® NE 30D (copolymer dispersion of ethylacrylate, methyl methacrylate), and EUDRAGIT® NM 30D (copolymerdispersion of ethyl acrylate, methyl methacrylate), to improvemechanical strength (tensile strength). The membrane can further includehydrophilic polymer and, optionally, water-soluble nonionic polymer thatact as a pore former, to modify its elasticity, permeability, andtensile strength.

In certain embodiments, the permeable elastic membrane can providedesired characteristics for drug release and tensile strength towithstand peristalsis and mechanical contractility of the stomach(shear). The combination of a water-soluble hydrophilic polymer in thecore, and the unique permeable elastic membrane formed over the tabletcore by the coating of a homogeneous dispersion of at least one ofEUDRAGIT® RL 30D and EUDRAGIT® RS 30D (collectively “dispersions ofammonium salts of polymethacrylate copolymers”) to improve permeability,and at least one of KOLLICOAT® SR 30D, EUDRAGIT® NE 30D, and EUDRAGIT®NM 30D (collectively “neutral polymethacrylate copolymer dispersions”)to improve mechanical strength (tensile strength), can provide thedesired extended drug release while maintaining the integrity of thecore in an expanded state, thus extending the gastric residence time andpreventing the dosage form from being emptied from the stomach untilsubstantial or complete release of the drug, usually after a prolongedperiod.

In certain embodiments, the water-insoluble polymers in the permeableelastic membrane can comprise at least one of EUDRAGIT® RL PO and/orEUDRAGIT® RS PO (i.e., solutions of ammonium polymethacrylatecopolymers). In certain embodiments, the permeable elastic membrane canbe formed over the core by coating the core with a solution of EUDRAGIT®RL PO (copolymer of ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chloride (1:2:0.2) and/or EUDRAGIT®RS PO (copolymer of ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chloride (1:2:0.1), a plasticizer,and talc.

In certain embodiments, the membrane can include a water-insolublepolymer, a plasticizer, and at least one pore former comprising awater-soluble nonionic polymer. In certain embodiments, the pore formersand plasticizers can modify membrane elasticity, permeability, andtensile strength. In certain embodiments, the membrane can exclude anypore former. In certain embodiments, examples of insoluble permeablecomponents of the permeable elastic membrane include, but are notlimited to, copolymers of ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chlorides (e.g., EUDRAGIT® RL 30D orEUDRAGIT® RS 30D, EUDRAGIT® RS PO, EUDRAGIT® RL PO); cellulose acetatephthalate; ethyl cellulose; and hypromellose acetate succinate.

In certain embodiments, examples of insoluble components of thepermeable elastic membrane that provide elasticity to the membraneinclude, but are not limited to, copolymers of ethyl acrylate and methylmethacrylate (e.g., EUDRAGIT® NE 30D, EUDRAGIT® NM 30D), polyvinylacetates (e.g., KOLLICOAT® SR 30D), thermoplastic polyurethanes,ethylene-vinyl acetate, and polydimethyl siloxane.

In certain embodiments, the permeable elastic membrane can be a coatingof a solution of EUDRAGIT® RL PO and/or EUDRAGIT® RS PO. In certainembodiments, the core can be coated with a solution of EUDRAGIT® RL POand/or EUDRAGIT® RS PO in acetone and water mixture.

In certain embodiments, the coating dispersion can include at least oneof EUDRAGIT® RL PO and EUDRAGIT® RS PO (collectively “solutions ofammonium polymethacrylate copolymer”) to improve permeability, and atleast one plasticizer to improve mechanical strength (tensile strength).In certain embodiments, powder forms of EUDRAGIT®, e.g., EUDRAGIT® RL POand EUDRAGIT® RS PO, are preferred over EUDRAGIT® dispersions, e.g.,EUDRAGIT® RS 30D and EUDRAGIT® RL 30D.

In certain embodiments, the permeability of the permeable elasticmembrane can be adjusted to provide a floating lag time of less thanabout 10 minutes and floating time of about 1 hour to about 24 hours. Incertain embodiments, the gastroretentive pyridostigmine tablets of thedisclosure can comprise a membrane containing ammonium polymethacrylatecopolymer, e.g., EUDRAGIT® RL PO or EUDRAGIT®RS PO, and can exhibit afloating lag time of about 30 minutes or less and floating time of about1 hour to about 24 hours. In certain embodiments, the ammoniumpolymethacrylate copolymer can be present in an amount of between about70% and about 95% w/w of the membrane composition to provide desiredtensile strength, and elasticity for rapid expansion of the membrane. Incertain embodiments, plasticizer can be present in an amount of betweenabout 5 wt % and about 25 wt %, between about 10 wt % and about 20 wt %,between about 10 wt % and about 15 wt %, and any intermediate rangesthere in, of the membrane composition to provide desired tensilestrength, and elasticity for rapid expansion of the membrane. In certainembodiments, the plasticizer is present in an amount of at least about10 wt %, at least about 11 wt %, at least about 12 wt %, at least about13 wt %, at least about 14 wt %, at least about 15 wt %, at least about16 wt %, at least about 17 wt %, at least about 18 wt %, at least about19 wt %, at least about 20 wt %, at least about 21 wt %, at least about22 wt %, at least about 23 wt %, at least about 24 wt %, and at leastabout 25 wt % of the membrane composition.

In certain embodiments, the membrane can further include an anti-tackingagent selected from the group consisting of talc, colloidal silicondioxide, magnesium trisilicate, powdered cellulose, starch, and tribasiccalcium phosphate. In certain embodiments, the anti-tacking agent can becolloidal silicon dioxide. In certain embodiments, the anti-tackingagent can be present in an amount of about 5 wt % to about 30 wt % ofthe membrane composition. In certain embodiments, the glidant is presentin an amount of about 5 wt %, about 10 wt %, about 15 wt %, about 20 wt%, about 25 wt %, about 30 wt %, or any intermediate values therein, byweight of the membrane composition.

In certain embodiments, the membrane can expand the dosage form in about30 minutes to a size that prevents its passage through the pyloricsphincter, and the hydrophilic core, surrounded by the membrane, canswell with imbibition and absorption of fluid and assist the membrane inproviding an extended release of the drug. In certain embodiments, themembrane can be highly elastic and flexible due to the presence of atleast one plasticizer and can expand rapidly with an outward pressure onthe membrane from the generated CO₂ gas.

In certain embodiments, the membrane can provide an extended release ofthe drug for at least about eighteen hours, e.g., about twenty-fourhours.

6.2.2.2 Core

In certain embodiments, the core can comprise pyridostigmine or apharmaceutically acceptable salt thereof, an acid, a gas-generatingagent, a disintegrant/wicking agent, and at least one swellablewater-soluble hydrophilic polymer.

In certain embodiments, the swellable water-soluble hydrophilic polymerin the core can comprise hydroxypropyl methylcellulose (BENECEL™ K4M PHDC), hydroxypropyl cellulose, methyl cellulose (METHOCEL K100 PremiumLVCR), a polyethylene oxide polymer, a carbomer, sodium alginate, ormixtures thereof. In certain embodiments, the water-soluble polymer canbe BENECEL™ K4M PH DC. In certain embodiments, the swellablewater-soluble hydrophilic polymer can be METHOCEL K100 Premium LVCR. Incertain embodiments, the swellable water-soluble hydrophilic polymer canbe a mixture of METHOCEL K100 Premium LVCR and BENECEL K4M PH DC.

In certain embodiments, the core comprises gas-generating agents thatcan generate CO₂ on interaction with acid. Examples of gas-generatingagents that can be used in the compositions of the present disclosureinclude, but are not limited to, all organic and inorganic strong andweak bases, e.g., carbonate and bicarbonate salts of alkali and alkalineearth metals, that can interact with stomach acid for in situ gasgeneration. In certain embodiments, the gas-generating agent can besodium bicarbonate, sodium carbonate, magnesium carbonate, and/orcalcium carbonate. In certain embodiments, a mixture of calciumcarbonate and sodium bicarbonate can provide desired sustained releaseof CO₂. In certain embodiments, the gas-generating agent can be presentin an amount of at about 5 wt % to about 50 wt % of core. In certainembodiments, the gas-generating agent can be present in an amount ofabout 5 wt %, about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt%, about 30 wt %, about 35 wt %, about 40 wt %, about 45 wt %, about 50wt %, or any intermediate values therein, based on the total weight ofthe core.

In certain embodiments, the core can comprise an acid to achieve rapidfloating and expansion of the tablet, regardless of the gastric pH. Incertain embodiments, the acids include, but are not limited to, succinicacid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid,tartaric acid, boric acid, benzoic acid, or mixtures thereof. In certainembodiments, the acid can be succinic acid. In certain embodiments, theacid can be present in an amount of between 0 wt % and about 20 wt % ofthe core. In certain embodiments, the acid can be present in an amountof about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt%, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %,about 10 wt %, about 12.5 wt %, about 15 wt %, about 20 wt %, or anyintermediate values therein, based on the total weight of the core.

In certain embodiments, the acid is succinic acid and the gas-generatingagent is a mixture of sodium bicarbonate and calcium carbonate.

In certain embodiments, the core can comprise a wickingagent/disintegrant selected from a group comprising, but not limited to,croscarmellose sodium; sodium starch glycolate; low-substitutedhydroxypropyl cellulose; a mixture of 90% mannitol, 5% crospovidone, and5% polyvinyl acetate (LUDIFLASH®); a coprocessed blend of mannitol,starch, crospovidone, croscarmellose sodium, colloidal silica, andsilica (PHARMABURST®); microcrystalline cellulose; alginic acid; andmixtures thereof. In certain embodiments, the wicking agent can becrospovidone. In certain embodiments, the wicking agent is present in anamount of about 5 wt % to about 25 wt % of the core. In certainembodiments, the wicking agent is present in amount of about 5 wt %,about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, or anyintermediate values therein, based on the total weight of the core.

In certain embodiments, the core can further include at least onelubricant selected from the group comprising magnesium stearate,glyceryl monostearates, palmitic acid, talc, carnauba wax, calciumstearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zincstearate, polyoxyethylene monostearates, calcium silicate, silicondioxide, hydrogenated vegetable oils and fats, stearic acid, and anycombinations thereof. In certain embodiments, the lubricant is magnesiumstearate. In certain embodiments, the lubricant can be present in anamount of about 0.1 wt % to about 2 wt % of the core. In certainembodiments, the lubricant can be present in an amount of about 0.5 wt%, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about1.0 wt %, about 1.1 wt %, about 1.2 wt %, about 1.3 wt %, about 1.4 wt%, about 1.5 wt %, about 1.6 wt %, about 1.7 wt %, about 1.8 wt %, about1.9 wt %, about 2.0 wt %, or any intermediate values therein, based onthe total weight of the core.

In certain embodiments, the core can include at least one glidantselected from the group comprising talc, colloidal silicon dioxide,magnesium trisilicate, powdered cellulose, starch, and tribasic calciumphosphate. In certain embodiments, the glidant can be colloidal silicondioxide. In certain embodiments, the glidant can be present in an amountof about 0.1 wt % to about 2 wt % based on the total weight of the core.In certain embodiments, the glidant can be present in an amount of about0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt%, about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about1 wt %, about 1.5 wt %, about 2 wt %, or any intermediate valuestherein, based on the total weight of the core.

In certain embodiments, the core can further comprise afiller/compression aid. In certain embodiments, mannitol can be used asa filler/compression aid. In certain embodiments, mannitol can be usedas an osmotic agent. In certain embodiments, mannitol can be present inan amount of about 1 wt % to about 40 wt % based on the total weight ofthe core.

In certain embodiments, the core can further comprise at least one colorpigment. In certain embodiments, the core can include at least onepigment comprising iron oxide or lake-based colors. In certainembodiments, the pigment can be a lake-based color. In certainembodiments, the pigment can be an iron oxide pigment, e.g., oxidepigment black or Red blend. In certain embodiments, the pigment can bepresent in an amount of about 0.5 wt % to about 2 wt % based on thetotal weight of the core.

6.2.2.3 Immediate Release Drug Layer

In certain embodiments, the gastroretentive pyridostigmine compositions(e.g., tablets) of the disclosure can include an immediate releaseportion and an extended release portion to provide a biphasic release ofpyridostigmine or a pharmaceutically acceptable salt thereof. In certainembodiments, the immediate release portion can be present as animmediate release drug layer. In certain embodiments, the immediaterelease drug layer can cover at least a portion of the functionalcoat/permeable membrane. In certain embodiments, the immediate releasedrug layer can comprise pyridostigmine or a pharmaceutically acceptablesalt thereof and a binder.

In certain embodiments, the binder(s) can be selected from the groupconsisting of, but not limited to, povidone K 90, hypromellose, starch,acacia, gellan gum, low viscosity hydroxypropyl cellulose,methylcellulose, sodium methylcellulose, polyvinyl alcohol, polyvinylacetates (e.g., KOLLICOAT® SR), polyethylene oxide (e.g., POLYOX®),polyethylene glycol, alginates, and pegylated polyvinyl alcohol. Incertain embodiments, the binder can be hydroxypropyl cellulose. Incertain embodiments, the binders can be present in an amount of about0.5 wt % to about 30 wt % of the amount of drug in the immediate releasedrug layer. In certain embodiments, the binders can be present in anamount of about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt%, about 0.9 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt%, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %,about 10 wt %, about 15 wt %, about 20 wt %, about 25 wt %, about 30 wt%, or any intermediates values therein, of the amount of drug in theimmediate release drug layer.

6.2.2.4 Additional Coats

In certain embodiments, the gastroretentive tablets of the disclosurefurther can include a seal coat between the core and the permeableelastic membrane and/or between the permeable elastic membrane and theimmediate release drug layer. In certain embodiments, the seal coat cancover at least a portion of the membrane. In certain embodiments, theseal coat can comprise one or more water-soluble hydrophilic polymersselected from the group consisting of a polyvinyl alcohol-based polymer(OPADRY® white), methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and mixtures thereof. Incertain embodiments, the seal coat can comprise a mixture ofhydroxypropyl methylcellulose and hydroxypropyl cellulose. In certainembodiments, the seal coat can be present in an amount of about 0.5 wt %to about 5 wt % of the uncoated core, membrane-coated core, or core withdrug layer. In certain embodiments, the seal coat can be present in anamount of about 0.5 wt %, about 1 wt %, about 1.5 wt %, about 2 wt %,about 2.5 wt %, about 3 wt %, about 3.5 wt %, about 4 wt %, about 4.5 wt%, about 5 wt %, or any intermediate values therein, of the uncoatedcore, membrane-coated core, or core with drug layer.

In certain embodiments, the gastroretentive tablets of the disclosurefurther includes an over coat. In certain embodiments, the over coatcovers at least a portion of the permeable elastic membrane. In certainembodiments, the over coat can completely cover the permeable elasticmembrane. In certain embodiments, the over coat can be the outermostcoat. In certain embodiments, the over coat can comprise one or morewater-soluble hydrophilic polymers selected from the group consisting ofmethylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, and polyvinyl alcohol-based OPADRY®white.

In certain embodiments, the gastroretentive tablets of the disclosurecan include at least one laser-drilled orifice/hole that passes throughthe permeable elastic membrane/functional coat and seal coat. In certainembodiments, the gastroretentive dosage forms of the disclosure includemultiple laser-drilled orifices/holes.

6.2.2.5 Compositions

In certain embodiments, the present disclosure provide for agastroretentive dosage form comprising an extended release portion andan immediate release portion, wherein the extended release portioncomprises a core comprising pyridostigmine bromide, an acid, agas-generating agent, and a water-soluble hydrophilic polymer thatswells via imbibition of gastric fluid, and a permeable elastic membranesurrounding the core and comprising a plasticizer, and a copolymer basedon ethyl acrylate, methyl methacrylate, and trimethylammonioethylmethacrylate chloride, and the immediate release portion comprises animmediate release drug layer containing pyridostigmine bromide, andwherein the dosage form provides an extended release, with reducedinitial burst release, of pyridostigmine bromide, for at least about 14hours. In certain embodiments, the core of the dosage form of thepresent disclosure includes a wicking agent selected from the groupconsisting of crospovidone; croscarmellose sodium; sodium starchglycolate; low-substituted hydroxypropyl cellulose; a mixture ofmannitol, crospovidone, and polyvinyl acetate; a coprocessed blend ofmannitol, starch, crospovidone, croscarmellose sodium, colloidal silica,and silica; microcrystalline cellulose; alginic acid; and mixturesthereof. In certain other embodiments, the core of the dosage formcomprises crospovidone as a wicking agent. In certain embodiments, thedosage form of the present disclosure comprises a water-solublehydrophilic polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, apolyethylene oxide polymer, a carbomer, sodium alginate, and mixturesthereof. In particular embodiments, the water-soluble hydrophilicpolymer is hydroxypropyl methylcellulose. In certain other embodiments,the water-soluble hydrophilic polymer is methyl cellulose. In certainother embodiments, the water-soluble hydrophilic polymer is a mixture ofhydroxypropyl methylcellulose and methyl cellulose. In certainembodiments, the dosage form of the present disclosure comprises agas-generating agent selected from the group consisting of NaHCO₃,CaCO₃, and a mixture thereof. In certain embodiments, the gas-generatingagent is a mixture of NaHCO₃ and CaCO₃. In certain embodiments, thedosage form of the present disclosure comprises a plasticizer isselected from the group consisting of triethyl citrate, triacetin,polyethylene glycol, propylene glycol, dibutyl sebacate, and mixturesthereof. In particular embodiments, the plasticizer is triethyl citrate.In certain embodiments, the permeable elastic membrane of the dosageform of the present disclosure is at least partially covered by theimmediate release drug layer. In certain embodiments, the presentdisclosure provides for a dosage form that further includes a seal coatbetween the immediate release drug layer and the permeable elasticmembrane. In certain embodiments, the seal coat of the dosage form orthe present disclosure comprises a water-soluble polymer selected fromthe group consisting of a polyvinyl alcohol-based polymer, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, or a mixture thereof. In certainembodiments, the dosage form of the present disclosure further includesan over coat over the immediate release drug layer. In particularembodiments, the over coat comprises a water-soluble polymer selectedfrom a group consisting of a polyvinyl alcohol-based polymer, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, or a mixture thereof.

In certain embodiments, the present disclosure provides for an extendedrelease gastroretentive pyridostigmine tablet comprising an extendedrelease portion and an immediate release portion, wherein the extendedrelease portion comprises a core comprising pyridostigmine bromide, anacid, a gas-generating agent, and a water-soluble hydrophilic polymerthat swells via imbibition of gastric fluid; and a permeable elasticmembrane, surrounding the core, comprising a plasticizer, and acopolymer based on ethyl acrylate, methyl methacrylate, andtrimethylammonioethyl methacrylate chloride, and the immediate releaseportion comprises an immediate release drug layer containingpyridostigmine bromide, and wherein the tablet is suitable for oncedaily administration and is administered as a single tablet/day. Incertain embodiments, the tablet of present disclosure comprises 100 mg,200 mg, 250 mg, 300 mg, or 350 mg of pyridostigmine bromide.

In certain embodiments, the water-soluble hydrophilic polymer of thetablet of the present disclosure is selected from the group consistingof hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, a polyethylene oxide polymer, a carbomer, sodium alginate,and mixtures thereof. In certain embodiments, the gas-generating agentof the tablet of the present disclosure comprises NaHCO₃, CaCO₃, or amixture thereof. In certain embodiments, the plasticizer of the tabletof the present disclosure is selected from the group consisting oftriethyl citrate, triacetin, polyethylene glycol, propylene glycol,dibutyl sebacate, and mixtures thereof. In certain embodiments, thetablet of the present disclosure further includes a wicking agentselected from the group consisting of crospovidone; croscarmellosesodium; sodium starch glycolate; low-substituted hydroxypropylcellulose; a mixture of mannitol, crospovidone, and polyvinyl acetate; acoprocessed blend of mannitol, starch, crospovidone, croscarmellosesodium, colloidal silica, and silica; microcrystalline cellulose;alginic acid; and mixtures thereof. In certain embodiments, thepermeable elastic membrane of the tablet of the present disclosure is atleast partially covered by the immediate release drug layer. In certainembodiments, the tablet of the present disclosure further includes aseal coat between the immediate release drug layer and the permeableelastic membrane. In certain embodiments, the seal coat of the tablet ofthe present disclosure comprises a water soluble polymer selected fromthe group consisting of a polyvinyl alcohol-based polymer, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, or a mixture thereof. In certainembodiments, the present disclosure provides for a tablet that furtherincludes an over coat over the immediate release drug layer. In certainembodiments, the overcoat of the tablets of the present disclosurecomprises a water-soluble polymer selected from a group consisting of apolyvinyl alcohol-based polymer, methyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, andmixtures thereof.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, a functional coat, and an overcoat. Incertain embodiment, the core of the pyridostigmine bromidegastroretentive tablets can comprise one or more of pyridostigminebromide, succinic acid, sodium bicarbonate, calcium carbonate,crospovidone, mannitol, hydroxypropyl methylcellulose, methylcellulose,fumed silica, magnesium stearate, and combinations thereof. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise from about 100 mg to about 250 mg, from about 150mg to about 200 mg, or about 180 mg of pyridostigmine bromide. Incertain embodiments, the core can further comprise from about 20 mg toabout 100 mg, from about 40 mg to about 80 mg, or from about 50 mg toabout 60 mg of succinic acid. In certain embodiments, the core canfurther comprise from about 20 mg to about 80 mg, from about 30 mg toabout 65 mg, or from about 45 mg to about 55 mg of sodium bicarbonate.In certain embodiments, the core can further comprise from about 40 mgto about 200 mg, from about 50 mg to about 150 mg, or from about 60 mgto about 130 mg of calcium carbonate. In certain embodiments, the corecan further comprise from about 50 mg to about 200 mg, or about 100 mgof crospovidone. In certain embodiments, the core can further comprisefrom about 100 mg to about 300 mg, from about 150 mg to about 250 mg, orabout 230 mg of mannitol. In certain embodiments, the core can furtheroptionally comprise from about 50 mg to about 350 mg, from about 100 mgto about 300 mg, or about 200 mg of hydroxypropyl methylcellulose. Incertain embodiments, the core can further optionally comprise from about150 mg to about 350 mg, or from about 200 mg to about 300 mg ofmethylcellulose. In certain embodiments, the core can further comprisefrom about 1 mg to about 10 mg, from about 2 mg to about 7 mg, or about4 mg of fumed silica. In certain embodiments, the core can furthercomprise from about 1 mg to about 15 mg, from about 5 mg to about 10 mg,or about 8 mg of magnesium stearate. In certain embodiments, thepyridostigmine bromide gastroretentive tablets can further comprise afunctional coat. In certain embodiments, the functional coat cancomprise one or more of triethyl citrate, talc, polyvinyl alcohol-basedpolymer, and combinations thereof. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan comprise from about 100 mg to about 200 mg, from about 125 mg toabout 175 mg, or from about 145 mg to about 150 mg of ammoniomethacrylate copolymer. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 30 mg, orfrom about 20 mg to about 25 mg of triethyl citrate. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about50 mg, from about 20 mg to about 40 mg, or from about 25 mg to about 35mg of talc. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can comprise an over coat. In certainembodiments, the over coat can comprise from about 5 mg to about 30 mg,from about 10 mg to about 20 mg, or about 15 mg of polyvinylalcohol-based polymer.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiment, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, methylcellulose, fumed silica, magnesiumstearate, and combinations thereof. In certain embodiments, the core ofthe pyridostigmine bromide gastroretentive tablets can comprise fromabout 50 mg to about 200 mg, from about 100 mg to about 150 mg, or about135 mg of pyridostigmine bromide. In certain embodiments, the core canfurther comprise from about 40 mg to about 150 mg, from about 60 mg toabout 100 mg, or from about 75 mg to about 85 mg of succinic acid. Incertain embodiments, the core can further comprise from about 20 mg toabout 80 mg, from about 30 mg to about 65 mg, or from about 45 mg toabout 55 mg of sodium bicarbonate. In certain embodiments, the core canfurther comprise from about 10 mg to about 100 mg, from about 25 mg toabout 75 mg, or from about 60 mg to 70 mg of calcium carbonate. Incertain embodiments, the core can further comprise from about 50 mg toabout 200 mg, or about 100 mg of crospovidone. In certain embodiments,the core can further comprise from about 100 mg to about 300 mg, fromabout 150 mg to about 275 mg, or from about 200 mg to about 255 mg ofmannitol. In certain embodiments, the core can further optionallycomprise from about 50 mg to about 250 mg, from about 100 mg to about 20mg, or about 150 mg of hydroxypropyl methylcellulose. In certainembodiments, the core can further comprise from about 100 mg to about450 mg, from about 150 mg to about 350 mg, or from about 150 mg to about300 mg of methylcellulose. In certain embodiments, the core can furthercomprise from about 1 mg to about 10 mg, from about 2 mg to about 8 mg,or from about 3 mg to about 5 mg of fumed silica. In certainembodiments, the core can further comprise from about 1 mg to about 15mg, from about 5 mg to about 10 mg, or about 8 mg of magnesium stearate.In certain embodiments, the pyridostigmine bromide gastroretentivetablets can further comprise a functional coat. In certain embodiments,the functional coat can comprise ammonio methacrylate copolymer,triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 100 mg to about 250 mg,from about 125 mg to about 200 mg, or from about 145 mg to about 190 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 50 mg, from about 15 mgto about 35 mg, from about 20 mg to about 30 mg of triethyl citrate. Incertain embodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about50 mg, from about 20 mg to about 40 mg, or from about 25 mg to about 30mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, methylcellulose, fumed silica, magnesiumstearate, and combinations thereof. In certain embodiments, the core ofthe pyridostigmine bromide gastroretentive tablets can comprise fromabout 50 mg to about 200 mg, from about 100 mg to about 150 mg, or about135 mg of pyridostigmine bromide. In certain embodiments, the core canfurther comprise from about 50 mg to about 150 mg, from about 80 mg toabout 30 mg, or about 125 mg of succinic acid. In certain embodiments,the core can further comprise from about 30 mg to about 100 mg, or fromabout 50 mg to about 75 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 25 mg to about 150mg, from about 50 mg to about 100 mg, or from about 60 mg to about 75 mgof calcium carbonate. In certain embodiments, the core can furthercomprise from about 100 mg to about 300 mg, from about 150 mg to about250 mg, or about 200 mg of crospovidone. In certain embodiments, thecore can further comprise from about 10 mg to about 200 mg, from about25 mg to about 50 mg, from about 100 mg to about 200 mg, or from about150 mg to about 175 mg of mannitol. In certain embodiments, the core canfurther optionally comprise from about 25 mg to about 150 mg, from about50 mg to about 125 mg, or about 100 mg of hydroxypropyl methylcellulose.In certain embodiments, the core can further comprise from about 50 mgto about 450 mg, or from about 100 mg to about 200 mg ofmethylcellulose. In certain embodiments, the core can further comprisefrom about 1 mg to about 10 mg, from about 2 mg to about 8 mg, or fromabout 3 mg to about 5 mg of fumed silica. In certain embodiments, thecore can further comprise from about 1 mg to about 15 mg, from about 5mg to about 10 mg, or about 8 mg of magnesium stearate. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a functional coat. In certain embodiments, thefunctional coat can comprise one or more of ammonio methacrylatecopolymer, triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 250 mg,from about 100 mg to about 200 mg, or from about 125 mg to about 150 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 40 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 20 mg to about 40 mg, or from about 25 mg toabout 35 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, methylcellulose, fumed silica, magnesiumstearate, and combinations thereof. In certain embodiments, the core ofthe pyridostigmine bromide gastroretentive tablets can comprise fromabout 100 mg to about 250 mg, from about 150 mg to about 200 mg, orabout 180 mg of pyridostigmine bromide. In certain embodiments, the corecan further comprise from about 50 mg to about 150 mg, from about 80 mgto about 30 mg, or about 125 mg of succinic acid. In certainembodiments, the core can further comprise from about 30 mg to about 100mg, or from about 50 mg to about 75 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 25 mg to about 150mg, from about 70 mg to about 125 mg, or about 100 mg of calciumcarbonate. In certain embodiments, the core can further comprise fromabout 100 mg to about 300 mg, from about 150 mg to about 250 mg, orabout 200 mg of crospovidone. In certain embodiments, the core canfurther comprise from about 50 mg to about 200 mg, from about 75 mg toabout 150 mg, or from about 100 mg to about 125 mg of mannitol. Incertain embodiments, the core can further optionally comprise from about25 mg to about 150 mg, from about 50 mg to about 125 mg, or about 100 mgof hydroxypropyl methylcellulose. In certain embodiments, the core canfurther comprise from about 50 mg to about 300 mg, or from about 100 mgto about 200 mg of methylcellulose. In certain embodiments, the core canfurther comprise from about 1 mg to about 10 mg, from about 2 mg toabout 8 mg, or from about 3 mg to about 5 mg of fumed silica. In certainembodiments, the core can further comprise from about 1 mg to about 15mg, from about 5 mg to about 10 mg, or about 8 mg of magnesium stearate.In certain embodiments, the pyridostigmine bromide gastroretentivetablets can further comprise a functional coat. In certain embodiments,the functional coat can comprise one or more of ammonio methacrylatecopolymer, triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 200 mg,from about 75 mg to about 150 mg, or from about 100 mg to about 125 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 40 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 15 mg to about 40 mg, or from about 20 mg toabout 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, methylcellulose, fumed silica, magnesiumstearate, and combinations thereof. In certain embodiments, the core ofthe pyridostigmine bromide gastroretentive tablets can comprise fromabout 150 mg to about 400 mg, from about 200 mg to about 450 mg, or fromabout 250 to about 310 mg of pyridostigmine bromide. In certainembodiments, the core can further comprise from about 25 mg to about 125mg, from about 50 mg to about 100 mg, or from about 75 mg to about 90 mgof succinic acid. In certain embodiments, the core can further comprisefrom about 30 mg to about 100 mg, or from about 50 mg to about 75 mg ofsodium bicarbonate. In certain embodiments, the core can furthercomprise from about 20 mg to about 100 mg, from about 40 mg to about 80mg, or from about 60 mg to about 75 mg of calcium carbonate. In certainembodiments, the core can further comprise from about 50 mg to about 150mg, from about 75 mg to about 125 mg, or about 100 mg of crospovidone.In certain embodiments, the core can further comprise from about 25 mgto about 175 mg, from about 50 mg to about 150 mg, or from about 70 mgto about 125 mg of mannitol. In certain embodiments, the core canfurther optionally comprise from about 50 mg to about 200 mg, from about100 mg to about 175 mg, or about 150 mg of hydroxypropylmethylcellulose. In certain embodiments, the core can further comprisefrom about 50 mg to about 200 mg, from about 100 mg to about 175 mg, orabout 150 mg of methylcellulose. In certain embodiment, the core canfurther comprise from about 1 mg to about 20 mg, from about 5 mg toabout 15 mg, or about 10 mg of fumed silica. In certain embodiment, thecore can further comprise from about 5 mg to about 20 mg, from about 10mg to about 15 mg, or about 12 mg of magnesium stearate. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a functional coat. In certain embodiments, thefunctional coat can comprise one or more of ammonio methacrylatecopolymer, triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 200 mg,from about 75 mg to about 175 mg, or from about 125 mg to about 150 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 40 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 15 mg to about 40 mg, or from about 25 mg toabout 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, a functional coat, a seal coat, a druglayer and an over coat. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise one or moreof pyridostigmine bromide, succinic acid, sodium bicarbonate, calciumcarbonate, crospovidone, mannitol, hydroxypropyl methylcellulose,methylcellulose, fumed silica, magnesium stearate, oxide pigment black,and combinations thereof. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 100 mg to about 150 mg, or about 135mg of pyridostigmine bromide. In certain embodiments, the core canfurther comprise from about 25 mg to about 125 mg, from about 50 mg toabout 100 mg, or from about 75 mg to about 90 mg of succinic acid. Incertain embodiments, the core can further comprise from about 30 mg toabout 100 mg, from about 50 mg to about 75 mg, or about 55 mg of sodiumbicarbonate. In certain embodiments, the core can further comprise fromabout 20 mg to about 100 mg, from about 40 mg to about 80 mg, or fromabout 60 mg to about 70 mg of calcium carbonate. In certain embodiments,the core can further comprise from about 50 mg to about 150 mg, fromabout 75 mg to about 125 mg, or about 100 mg of crospovidone. In certainembodiments, the core can further comprise from about 150 mg to about400 mg, from about 200 mg to about 350 mg, or from about 250 mg to about300 mg of mannitol. In certain embodiments, the core can furtheroptionally comprise from about 50 mg to about 200 mg, from about 100 mgto about 175 mg, or about 150 mg of hydroxypropyl methylcellulose. Incertain embodiments, the core can further comprise from about 50 mg toabout 200 mg, from about 100 mg to about 175 mg, or about 150 mg ofmethylcellulose. In certain embodiments, the core can further comprisefrom about 1 mg to about 20 mg, from about 5 mg to about 15 mg, or about10 mg of fumed silica. In certain embodiments, the core can furthercomprise from about 5 mg to about 20 mg, from about 10 mg to about 15mg, or about 12 mg of magnesium stearate. In certain embodiments, thecore can further optionally comprise from about 5 mg to about 20 mg, orfrom about 10 mg to about 15 mg, or about 12 mg of oxide pigment black.In certain embodiments, the pyridostigmine bromide gastroretentivetablets can further comprise a functional coat. In certain embodiments,the functional coat can comprise one or more of ammonio methacrylatecopolymer, triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 200 mg,from about 75 mg to about 175 mg, or from about 125 mg to about 150 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 40 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 15 mg to about 40 mg, or from about 25 mg toabout 30 mg of talc. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a seal coat. In certainembodiments the seal coat can comprise from about 1 mg to about 20 mg,from about 5 mg to about 15 mg, or about 10 mg of polyvinylalcohol-based polymer. In certain embodiments, the pyridostigminebromide gastroretentive tablets can further comprise a drug layer. Incertain embodiments, the drug layer can comprise pyridostigmine bromide,hydroxypropyl cellulose, and combinations thereof. In certainembodiments, the drug layer can comprise from about 10 mg to about 100mg, from about 25 mg to about 75 mg, or from about 40 mg to about 50 mgof pyridostigmine bromide. In certain embodiments, the drug layer cancomprise from about 1 mg to about 20 mg, from about 5 mg to about 15 mg,or from about 8 mg to about 12 mg of hydroxypropyl cellulose. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise an over coat. In certain embodiments, the over coat cancomprise from about 20 mg to about 60 mg, from about 30 mg to about 50mg, or about 40 mg of polyvinyl alcohol-based polymer.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, methylcellulose, fumed silica, magnesiumstearate, and combinations thereof. In certain embodiments, the core ofthe pyridostigmine bromide gastroretentive tablets can comprise fromabout 200 mg to about 400 mg, from about 250 mg to about 350 mg, or fromabout 285 mg, to about 315 mg of pyridostigmine bromide. In certainembodiments, the core can further comprise from about 25 mg to about 125mg, from about 50 mg to about 100 mg, or from about 75 mg to about 90 mgof succinic acid. In certain embodiments, the core can further comprisefrom about 30 mg to about 100 mg, or from about 50 mg to about 75 mg ofsodium bicarbonate. In certain embodiments, the core can furthercomprise from about 20 mg to about 100 mg, from about 40 mg to about 80mg, or from about 60 mg to about 75 mg of calcium carbonate. In certainembodiments, the core can further comprise from about 50 mg to about 150mg, from about 75 mg to about 125 mg, or about 100 mg of crospovidone.In certain embodiments, the core can further optionally comprise fromabout 25 mg to about 175 mg, from about 50 mg to about 150 mg, fromabout 60 mg to about 100 mg, or from about 70 mg to about 85 mg ofmannitol. In certain embodiments, the core can further comprise fromabout 100 mg to about 300 mg, from about 125 mg to about 250 mg, or fromabout 150 mg to about 200 mg of hydroxypropyl methylcellulose. Incertain embodiments, the core can further comprise from about 100 mg toabout 300 mg, from about 125 mg to about 250 mg, or from about 150 mg toabout 200 mg of methylcellulose. In certain embodiments, the core canfurther comprise from about 1 mg to about 20 mg, from about 5 mg toabout 15 mg, or about 10 mg of fumed silica. In certain embodiments, thecore can further comprise from about 5 mg to about 20 mg, from about 10mg to about 15 mg, or about 12 mg of magnesium stearate. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a functional coat. In certain embodiments, thefunctional coat can comprise one or more of ammonio methacrylatecopolymer, triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 200 mg,from about 75 mg to about 175 mg, or from about 125 mg to about 150 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 40 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 15 mg to about 40 mg, or from about 25 mg toabout 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, methylcellulose, fumed silica, magnesiumstearate, and combinations thereof. In certain embodiments, the core ofthe pyridostigmine bromide gastroretentive tablets can comprise fromabout 100 mg to about 300 mg, from about 175 mg to about 275 mg, fromabout 195 mg to about 210 mg, or from about 225 mg to about 260 mg ofpyridostigmine bromide. In certain embodiments, the core can furthercomprise from about 25 mg to about 125 mg, from about 50 mg to about 100mg, or from about 75 mg to about 90 mg of succinic acid. In certainembodiments, the core can further comprise from about 30 mg to about 100mg, or from about 50 mg to about 75 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 20 mg to about 100mg, from about 40 mg to about 80 mg, or from about 60 mg to about 75 mgof calcium carbonate. In certain embodiments, the core can furthercomprise from about 50 mg to about 150 mg, from about 75 mg to about 125mg, or about 100 mg of crospovidone. In certain embodiments, the corecan further optionally comprise from about 50 mg to about 200 mg, fromabout 100 mg to about 175 mg, from about 120 mg to about 125 mg, or fromabout 120 mg to about 175 mg of mannitol. In certain embodiments, thecore can further comprise from about 100 mg to about 300 mg, from about125 mg to about 250 mg, or from about 150 mg to about 215 mg ofhydroxypropyl methylcellulose. In certain embodiments, the core canfurther comprise from about 100 mg to about 300 mg, from about 125 mg toabout 250 mg, or from about 150 mg to about 215 mg of methylcellulose.In certain embodiments, the core can further comprise from about 1 mg toabout 20 mg, from about 5 mg to about 15 mg, or about 10 mg of fumedsilica. In certain embodiments, the core can further comprise from about5 mg to about 20 mg, from about 10 mg to about 15 mg, or about 12 mg ofmagnesium stearate. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise one or more ofammonio methacrylate copolymer, triethyl citrate, talc, and combinationsthereof. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 75 mg to about 175 mg, or from about125 mg to about 150 mg of ammonio methacrylate copolymer. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about40 mg, from about 15 mg to about 30 mg, or from about 20 mg to about 25mg of triethyl citrate. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 40 mg, orfrom about 25 mg to about 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, and a functional coat. In certainembodiments, the core of the pyridostigmine bromide gastroretentivetablets can comprise one or more of pyridostigmine bromide, succinicacid, sodium bicarbonate, calcium carbonate, crospovidone, mannitol,hydroxypropyl methylcellulose, methylcellulose, fumed silica, magnesiumstearate, and combinations thereof. In certain embodiments, the core ofthe pyridostigmine bromide gastroretentive tablets can comprise fromabout 50 mg to about 200 mg, from about 70 mg to about 170 mg, or fromabout 100 mg to about 160 mg of pyridostigmine bromide. In certainembodiments, the core can further comprise from about 25 mg to about 125mg, from about 50 mg to about 100 mg, or from about 75 mg to about 90 mgof succinic acid. In certain embodiments, the core can further comprisefrom about 30 mg to about 100 mg, or from about 50 mg to about 75 mg ofsodium bicarbonate. In certain embodiments, the core can furthercomprise from about 20 mg to about 100 mg, from about 40 mg to about 80mg, or from about 60 mg to about 75 mg of calcium carbonate. In certainembodiments, the core can further comprise from about 50 mg to about 150mg, from about 75 mg to about 125 mg, or about 100 mg of crospovidone.In certain embodiments, the core can further optionally comprise fromabout 200 mg to about 350 mg, from about 210 mg to about 310 mg, or fromabout 220 to about 280 mg of mannitol. In certain embodiments, the corecan further comprise from about 100 mg to about 300 mg, from about 125mg to about 250 mg, or from about 150 mg to about 200 mg ofhydroxypropyl methylcellulose. In certain embodiments, the core canfurther comprise from about 100 mg to about 300 mg, from about 125 mg toabout 250 mg, or from about 150 mg to about 200 mg of methylcellulose.In certain embodiments, the core can further comprise from about 1 mg toabout 20 mg, from about 5 mg to about 15 mg, or about 10 mg of fumedsilica. In certain embodiments, the core can further comprise from about5 mg to about 20 mg, from about 10 mg to about 15 mg, or about 12 mg ofmagnesium stearate. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise one or more ofammonio methacrylate copolymer, triethyl citrate, talc, and combinationsthereof. In certain embodiments, the functional coat of thepyridostigmine bromide gastroretentive tablets can comprise from about50 mg to about 200 mg, from about 75 mg to about 175 mg, or from about125 mg to about 150 mg of ammonio methacrylate copolymer. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can further comprise from about 10 mg to about40 mg, from about 15 mg to about 30 mg, or from about 20 mg to about 25mg of triethyl citrate. In certain embodiments, the functional coat ofthe pyridostigmine bromide gastroretentive tablets can further comprisefrom about 10 mg to about 50 mg, from about 15 mg to about 40 mg, orfrom about 25 mg to about 30 mg of talc.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, a functional coat, a seal coat, a druglayer, and an over coat. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise one or moreof pyridostigmine bromide, succinic acid, sodium bicarbonate, calciumcarbonate, crospovidone, mannitol, hydroxypropyl methylcellulose,methylcellulose, fumed silica, magnesium stearate, and combinationsthereof. In certain embodiments, the core of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg, to about 200 mg,from about 100 mg to about 150 mg, or about 135 mg of pyridostigminebromide. In certain embodiments, the core can further comprise fromabout 25 mg to about 125 mg, from about 50 mg to about 100 mg, or fromabout 75 mg to about 90 mg of succinic acid. In certain embodiments, thecore can further comprise from about 30 mg to about 100 mg, from about50 mg to about 75 mg, or about 55 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 20 mg to about 100mg, from about 40 mg to about 80 mg, or from about 60 mg to about 70 mgof calcium carbonate. In certain embodiments, the core can furthercomprise from about 50 mg to about 150 mg, from about 75 mg to about 125mg, or about 100 mg of crospovidone. In certain embodiments, the corecan further comprise from about 175 mg to about 300 mg, from about 200mg to about 275 mg, or from about 230 mg to 240 mg of mannitol. Incertain embodiments, the core can further optionally comprise from about50 mg to about 200 mg, from about 100 mg to about 175 mg, or about 150mg of hydroxypropyl methylcellulose. In certain embodiments, the corecan further comprise from about 50 mg to about 200 mg, from about 100 mgto about 175 mg, or about 150 mg of methylcellulose. In certainembodiments, the core can further comprise from about 1 mg to about 20mg, from about 5 mg to about 15 mg, or about 10 mg of fumed silica. Incertain embodiments, the core can further comprise from about 5 mg toabout 20 mg, from about 10 mg to about 15 mg, or about 12 mg ofmagnesium stearate. In certain embodiments, the core can furthercomprise from about 1 mg to about 20 mg, from about 5 mg to about 15 mg,or from about 7 mg to about 12 mg of oxide pigment black. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a functional coat. In certain embodiments, thefunctional coat can comprise one or more of ammonio methacrylatecopolymer, triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 200 mg,from about 75 mg to about 175 mg, or from about 125 mg to about 150 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 40 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 15 mg to about 40 mg, or from about 25 mg toabout 30 mg of talc. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a seal coat. In certainembodiments, the seal coat can comprise polyvinyl alcohol-based polymer.In certain embodiments, the seal coat can comprise from about 1 mg toabout 20 mg, from about 5 mg to about 15 mg, or about 10 mg of polyvinylalcohol-based polymer. In certain embodiments, the pyridostigminebromide gastroretentive tablets can further comprise a drug layer. Incertain embodiments, the drug layer can comprise pyridostigmine bromide,and hydroxypropyl cellulose. In certain embodiments, the drug layer cancomprise from about 20 mg to about 75 mg, from about 30 mg to about 60mg, or from about 40 mg to about 50 mg of pyridostigmine bromide. Incertain embodiments, the drug layer can further comprise from about 1 mgto about 20 mg, from about 5 mg to about 15 mg, or about 9 mg ofhydroxypropyl cellulose. In certain embodiments, the pyridostigminebromide gastroretentive tablets can further comprise an over coat. Incertain embodiments, the overcoat can comprise polyvinyl alcohol-basedpolymer. In certain embodiments, the over coat can comprise from about10 mg to about 60 mg, from about 20 mg to about 50 mg, or about 40 mg ofpolyvinyl alcohol-based polymer.

In certain embodiments, the pyridostigmine bromide gastroretentivetablets can comprise a core, a functional coat, a seal coat, a druglayer, and an over coat. In certain embodiments, the core of thepyridostigmine bromide gastroretentive tablets can comprise one or moreof pyridostigmine bromide, succinic acid, sodium bicarbonate, calciumcarbonate, crospovidone, mannitol, hydroxypropyl methylcellulose,methylcellulose, fumed silica, magnesium stearate, and combinationsthereof. In certain embodiments, the core of the pyridostigmine bromidegastroretentive tablets can comprise from about 25 mg to about 125 mg,from about 50 mg to about 100 mg, or about 75 mg of pyridostigminebromide. In certain embodiments, the core can further comprise fromabout 25 mg to about 125 mg, from about 50 mg to about 100 mg, or fromabout 75 mg to about 90 mg of succinic acid. In certain embodiments, thecore can further comprise from about 30 mg to about 100 mg, from about50 mg to about 75 mg, or about 55 mg of sodium bicarbonate. In certainembodiments, the core can further comprise from about 20 mg to about 100mg, from about 40 mg to about 80 mg, or from about 60 mg to about 70 mgof calcium carbonate. In certain embodiments, the core can furthercomprise from about 50 mg to about 150 mg, from about 75 mg to about 125mg, or about 100 mg of crospovidone. In certain embodiments, the corecan further comprise from about 200 mg to about 350 mg, from about 250mg to about 300 mg, or from about 270 mg to about 280 mg of mannitol. Incertain embodiments, the core can further optionally comprise from about50 mg to about 200 mg, from about 100 mg to about 175 mg, or about 150mg of hydroxypropyl methylcellulose. In certain embodiments, the corecan further comprise from about 50 mg to about 200 mg, from about 100 mgto about 175 mg, or about 150 mg of methylcellulose. In certainembodiments, the core can further comprise from about 1 mg to about 20mg, from about 5 mg to about 15 mg, or about 10 mg of fumed silica. Incertain embodiments, the core can further comprise from about 5 mg toabout 20 mg, from about 10 mg to about 15 mg, or about 12 mg ofmagnesium stearate. In certain embodiments, the core can furthercomprise from about 1 mg to about 20 mg, from about 5 mg to about 15 mg,or from about 7 mg to about 12 mg of oxide pigment black. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise a functional coat. In certain embodiments, thefunctional coat can comprise one or more of ammonio methacrylatecopolymer, triethyl citrate, talc, and combinations thereof. In certainembodiments, the functional coat of the pyridostigmine bromidegastroretentive tablets can comprise from about 50 mg to about 200 mg,from about 75 mg to about 175 mg, or from about 125 mg to about 150 mgof ammonio methacrylate copolymer. In certain embodiments, thefunctional coat of the pyridostigmine bromide gastroretentive tabletscan further comprise from about 10 mg to about 40 mg, from about 15 mgto about 30 mg, or from about 20 mg to about 25 mg of triethyl citrate.In certain embodiments, the functional coat of the pyridostigminebromide gastroretentive tablets can further comprise from about 10 mg toabout 50 mg, from about 15 mg to about 40 mg, or from about 25 mg toabout 30 mg of talc. In certain embodiments, the pyridostigmine bromidegastroretentive tablets can further comprise a seal coat. In certainembodiments, the seal coat can comprise polyvinyl alcohol-based polymer.In certain embodiments, the seal coat can comprise from about 1 mg toabout 20 mg, from about 5 mg to about 15 mg, or about 10 mg of polyvinylalcohol-based polymer. In certain embodiments, the pyridostigminebromide gastroretentive tablets can further comprise a drug layer. Incertain embodiments, the drug layer can comprise one of more ofpyridostigmine bromide, and hydroxypropyl cellulose and combinationsthereof. In certain embodiments, the drug layer can comprise from about10 mg to about 50 mg, from about 20 mg to about 40 mg, or about 30 mg ofpyridostigmine bromide. In certain embodiments, the drug layer canfurther comprise from about 1 mg to about 20 mg, from about 5 mg toabout 15 mg, or about 9 mg of hydroxypropyl cellulose. In certainembodiments, the pyridostigmine bromide gastroretentive tablets canfurther comprise an over coat. In certain embodiments, the overcoat cancomprise polyvinyl alcohol-based polymer. In certain embodiments, theover coat can comprise from about 10 mg to about 60 mg, from about 20 mgto about 50 mg, or about 40 mg of polyvinyl alcohol-based polymer.

6.2.2.6 Features of Gastroretentive Dosage Forms

The gastroretentive dosage forms (e.g., tablets) of the disclosurecombine the following two key attributes: gastric retention andcontinuous controlled drug delivery for up to about 24 hours. In certainembodiments, the disclosure provides gastroretentive tablets ofpyridostigmine that are suitable for providing stable pyridostigminelevels, with minimized initial burst release/dose dumping of the drug,for an extended period of time. This is particularly desirable formyasthenia gravis (MG) patients, as the constant level of pyridostigminehas been shown to improve therapeutic outcome and quality of life.Quality of life and compliance are also enhanced with the reduction orelimination of dose dumping of pyridostigmine, as experienced with thecurrently marketed ER formulation, and the concomitant reduction inundesirable side effects. FIG. 18 compares pharmacokinetic data forgastroretentive Tablet 8 (T₁), pellet compositions T₂ and T₃, andmarketed pyridostigmine products, e.g., MESTINON® tablets (60 mg/TID)(R₂) and MESTINON® TIMESPAN tablets (180 mg/QD)(R₁). FIG. 18demonstrates that bioavailability of gastroretentive Tablet 8 (T₁) iscomparable to MESTINON® (R₂) and MESTINON® TIMESPAN tablets (R₁) in thefed state. Pharmacokinetic data from FIG. 18 demonstrates thatgastroretentive tablets of the disclosure (T₁), by releasing the drug inthe upper GI tract, provide comparable bioavailability to marketedpyridostigmine products (R₁), and provide extended plasma concentrationprofiles for 24 hours. In certain embodiments, the gastroretentivetablets of the present disclosure provide for reduced initial burstrelease, of pyridostigmine bromide of at least 14 hours. In particularembodiments, the reduced initial burst release comprises an in vitrorelease of between about 20% and about 35% of the pyridostigmine bromidewithin 2 hours of dissolution in a dissolution medium comprising 50 mMacetate buffer with 100 mM NaCl.

The gastroretentive pyridostigmine tablets of the disclosure providesignificant therapeutic advantages over the currently marketedpyridostigmine products with respect to the following attributes: 1)enhanced control of symptoms associated with MG with once-a-day dosing,2) rapid onset of effect/reduced lag time and consistent blood levelsduring the daytime to treat progressive muscle weakness and fatigueknown to build up by the evening, 3) reduced initial drug concentration(e.g., reduced initial burst release; minimized initial burst release)sufficient to provide therapeutic effect without GI side effects, 4)lower, but still therapeutic, blood levels during the night for treatingnighttime symptoms and providing uninterrupted sleep, 5) improvedtolerability of the drug with reduced adverse events compared tofluctuating blood levels from an IR formulation, 6) reduced treatmentburden and improved adherence/compliance due to less frequent dosing,and 7) better patient satisfaction and quality of life with improvedfunctionality throughout the day and reduced reliance on caregivers.

In certain embodiments, the gastroretentive compositions of thedisclosure can comprise an immediate release portion and an extendedrelease portion. The immediate release portion can comprise an immediaterelease drug layer containing pyridostigmine bromide, and the extendedrelease portion can comprise a core coated with a permeable elasticmembrane. In certain embodiments, the core can comprise pyridostigminebromide, at least one gas-generating agent (e.g., sodium bicarbonate,calcium carbonate), at least one acid (e.g., succinic acid), and atleast one swellable water-soluble hydrophilic polymer. In certainembodiments, the gastroretentive tablets of the disclosure can includean orifice in the functional coat.

In certain embodiments, amounts of succinic acid and the gas-generatingagent(s) are optimized to minimize the floating lag time.

In certain embodiments, compositions of the disclosure include a sealcoat between the core and the functional coat. In certain otherembodiments, the compositions of the disclosure do not include a sealcoat between the core and the functional coat. Surprisingly, it wasobserved that absence of a seal coat between the tablet core and thefunctional coat resulted in minimizing the floating lag time. Tablets 8and 8A contained a seal coat between the tablet core and the functionalcoat; and Tablets 11/11A, 13/13A, and 15/15A did not include a seal coatbetween the tablet core and the functional coat. FIG. 10 comparesfloating lag times of Tablets 8, 11, 13, and 15, with and withoutorifice/hole, at 200 mg functional coating weight gain, and Tablets 8A,11A, 13A, and 15A, with and without orifice/hole, at 250 mg functionalcoating weight gain. The flotation studies were performed, usingRotating Bottle method at 5 rpm and 37° C., in 200 ml of a dissolutionmedium with pH 4.5 comprising 100 mM NaCl. FIG. 10 demonstrates thatTablets 8/8A, containing a seal coat, exhibit longer floating lag timescompared to tablets without a seal coat (Tablets 11/11A, 13/13A, and15/15A).

In certain embodiments, it was observed that tablets containing amixture of BENECEL® K4M PH DC (2700-5040 mPa.$) and METHOCEL® K100 PremLVCR (80-120 mPa.$) (Tablets 22, 23, and 34) provided a bettercontrolled release compared to tablets containing BENECEL® K4M PH DC(Tablet 8) alone. FIGS. 17 and 23 compare in vitro dissolution profilesof Tablets 8, 22, and 23; and Tablets 8 and 34, respectively. FIGS. 17and 23 demonstrate that Tablets 22, 23, and 34 (all containing a mixtureof BENECEL® K4M PH DC and METHOCEL® K100 Prem LVCR) provided bettercontrolled release compared to Tablet 8 (containing BENECEL® K4M PH DCalone).

FIGS. 20 and 21 compare pharmacokinetic data for gastroretentive Tablet34 (gastroretentive tablet with hole) and Tablet 35 (gastroretentivetablet without hole), respectively. FIGS. 20 and 21 demonstrate thatTablets 34 and 35 provide therapeutic plasma concentrations ofpyridostigmine bromide for at least about 22 hours.

In certain embodiments, the gastroretentive tablets of the disclosurecan include an immediate release portion and an extended releaseportion. In certain embodiments, the immediate release portion cancomprise an immediate release drug layer. FIG. 23 compares in vitrodissolution profiles of a tablet containing an immediate release druglayer (Tablet 34), a tablet with no immediate release drug layer (Tablet8), and a tablet of MESTINON® TIMESPAN. The figure demonstrates thatTablet 8 (without IR drug layer) exhibits minimized initial burstrelease; and Tablet 34 (with IR drug layer) provides an immediaterelease of a therapeutic amount of pyridostigmine bromide, with reducedinitial burst release (between about 20% and about 35% drug release inabout 2 hours) of the drug, compared to MESTINON® TIMESPAN.

FIG. 24 compares pharmacokinetic data for gastroretentive Tablet 34, atablet with a hole in the functional coat, under LF-LC breakfastconditions (Condition I) and HF-HC breakfast conditions (Condition II),and MESTINON® TIMESPAN (Condition II). FIG. 24 demonstrates thatMESTINON® TIMESPAN provides higher drug plasma concentrations betweenabout 0 and 5 hours compared to Tablet 34 under Conditions I and II.FIG. 24 further demonstrates that Tablet 34, under Conditions I and II,provides higher drug plasma concentrations of pyridostigmine bromideover an extended time period, e.g., about 7 hours or beyond, compared toMESTINON® TIMESPAN.

In certain embodiments, the compositions of the disclosure can comprisehorizontally compressed oval, modified oval, or capsule shapes for easyswallowing. In certain embodiments, the tablets can be compressed usingoval, modified oval, capsule shaped, or any other shaping tool. Incertain embodiments, the horizontally compressed tablets can comprise along axis having a length of between about 12 mm and about 22 mm, and ashort axis having a length of between about 8 mm and about 11 mm. Incertain embodiments, the tablets can have a long axis of about 12 mm,about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about18 mm, about 19 mm, about 20 mm, about 21 mm, about 22 mm, or anyintermediate lengths therein. In certain embodiments, the tablets canhave a short axis of about 8 mm, about 9 mm, about 10 mm, about 11 mm,or any intermediate lengths therein. In certain embodiments, thecompressed multilayered tablets can comprise a long axis having a lengthof about 20±2 mm, and a short axis having a length of between about 10±2mm. In certain embodiments, the initial tablet size (10 mm×19 mm) can bereasonably small for swallowability, and once swallowed, the tablet isdesigned for rapid generation of carbon dioxide (CO₂) within the core toincrease its buoyancy. Within 30 minutes of coming into contact withsimulated gastric medium, the tablet starts floating and transforms intoan oblong shape with major and minor axes having lengths of about 26 and18 mm respectively, which can be maintained for at least about 14 hours.

The gastroretentive tablets of the disclosure can comprise an expandinghydrophilic core and a rate-controlling membrane surrounding the core.The membrane can expand rapidly and provide a protective shell thatstretches upon hydration to accommodate the rapidly expandinghydrophilic core, and then acts as a rate-controlling membrane thatcontrols the release rate of the drug. In certain embodiments, thegastroretentive tablets of the disclosure, when in contact withsimulated gastric medium, can expand in about 60 minutes or less, to asize that prevents its passage through a pyloric sphincter. In certainembodiments, the gastroretentive tablets of the disclosure can float inabout 40 minutes or less, expand in about 60 minutes or less to a sizethat prevents its passage through pyloric sphincter, and provideextended release of pyridostigmine for about 24 hours. In certainembodiments, the gastroretentive tablets of the disclosure can float inabout 40 minutes or less in 50 mM pH 4.5 buffer containing 100 mM NaCl.In certain embodiments, the gastroretentive tablets of the disclosurecan float in about 35 minutes, about 34 minutes, about 33 minutes, about32 minutes, about 31 minutes, about 30 minutes, about 29 minutes, about28 minutes, about 27 minutes, about 26 minutes, about 25 minutes, about24 minutes, about 23 minutes, about 22 minutes, about 21 minutes, about20 minutes, about 19 minutes, about 18 minutes, about 17 minutes, about16 minutes, about 15 minutes or less, or any intermediate time periods,in 50 mM pH 4.5 buffer containing 100 mM NaCl. FIG. 10 providesflotation lag times of the compositions of the disclosure containing 200mg and 250 mg coating weight gains of the functional coat. In certainembodiments, the gastroretentive tablets of the disclosure can expand inless than about 60 minutes to a size that prevents their passage throughthe pyloric sphincter. In certain embodiments, the gastroretentivetablets of the disclosure can exhibit at least about 200% to about 800%volume gain from its original volume at 60 minutes, measured using aRotating Bottle method at about 5 rpm and about 37° C., in 200 ml of pH4.5 dissolution medium, containing about 100 mM NaCl. In certainembodiments, the gastroretentive tablets can exhibit about 200%, about250%, about 300%, about 350%, about 400%, about 450%, about 500%, about550%, about 600%, about 650%, about 700%, about 750%, about 800%, or anyintermediate values therein, volume gain from its original volume at 60minutes FIGS. 11-13 show volume expansions of the gastroretentivetablets of the disclosure, in pH 4.5 buffer containing about 100 mMNaCl. In certain embodiments, rapid expansion of the gastroretentivetablet can result from an initial expansion of the permeable elasticmembrane and a simultaneous swelling of the hydrophilic core to supportthe expanded membrane.

In certain embodiments, the hydrophilic core can swell to a size thatcan support the expanded permeable elastic membrane. In certainembodiments, the permeable elastic membrane can keep the core intact ina swollen condition for a sufficient period of time, and provides thedesired characteristics of drug release.

In certain embodiments, the gastroretentive tablets of the disclosuremarkedly improve absorption and bioavailability of pyridostigminebromide. In certain embodiments, the gastroretentive tablets of thedisclosure can provide gastric retention of pyridostigmine bromide forup to about 24 hours. In certain embodiments, the gastroretentivetablets of the disclosure can provide gastric retention ofpyridostigmine bromide for between, e.g., about 10 to about 24 hours,about 12 to about 24 hours, and about 14 to about 24 hours. In certainembodiments, the gastroretentive tablets of the disclosure can providegastric retention of pyridostigmine bromide for at least about 14 hours.In certain embodiments, the gastroretentive tablets of the disclosurecan maintain its integrity in a swollen state for a period of at leastabout 14 hours. In certain embodiments, the gastroretentive tablets ofthe disclosure can provide gastric retention of pyridostigmine bromidefor about 24 hours. Furthermore, as the drug diffuses out of the coreand the polymeric excipients in the core continue to swell, theplasticizer can leach out and the permeable elastic membrane can loseits integrity and starts to break, thereby allowing remnants of the drugformulation and the remaining contents to be expelled from the stomachat an appropriate time, e.g., after a prolonged period of drug release.FIG. 19 provides schematic and photographic representations of thegastroretentive tablets of the disclosure from its initial tablet formto its residue after complete drug release.

6.2.3. Pellets

In certain embodiments, compositions of the disclosure can be formulatedas granules or pellets. In certain embodiments, the compositions of thedisclosure can be formulated as pyridostigmine bromide pellets. Incertain embodiments, the pellets can comprise a pyridostigmine bromidecontaining core coated with a functional coat/membrane. In certainembodiments, the pyridostigmine bromide containing core can be furtherdrug-layered with a pyridostigmine bromide layer.

In certain embodiments, there can be a seal coat between thepyridostigmine bromide containing core and the functional coat/membrane,and/or between the pyridostigmine bromide layer and the functionalcoat/membrane. In certain embodiments, the functional coat can befurther coated with an immediate release drug layer comprisingpyridostigmine bromide. In certain embodiments, the immediate releasedrug layer is further coated with an overcoat. In certain embodiments,there is a seal coat between the immediate release drug layer and thefunctional coat, and/or between the immediate release drug layer and theovercoat.

In certain embodiments, the pellets can comprise a microcrystallinecellulose core (MCC), also known as a cellet. In certain embodiments,the MCC core or cellet is drug-layered with a pyridostigmine bromidelayer. In certain embodiments, the drug layer can be further coated witha functional coat. In certain embodiments, there can be a seal coatbetween the drug layer and the functional coat.

In certain embodiments, the drug layer over the pyridostigminecontaining core or the cellet core can comprise pyridostigmine bromide,a water-soluble polymer, a plasticizer, and/or an anti-tacking agent.

In certain embodiments, the water-soluble polymer can be one or more ofhypromellose and/or hydroxypropyl cellulose.

In certain embodiments, the anti-tacking agent can be one or more ofsilicon dioxide (SYLOID® 244FP), fumed silica (CAB-O-SIL®), talc,kaolin, or combinations thereof. In certain embodiments, the plasticizercomprises triethyl citrate, triacetin, polyethylene glycol, propyleneglycol, dibutyl sebacate, or combinations thereof. In certainembodiments, the plasticizer can be triethyl citrate. In certainembodiments, the plasticizer can be dibutyl sebacate.

In certain embodiments, the drug layer can comprise pyridostigminebromide, ethylcellulose, dibutyl sebacate, and talc. In certainembodiments, the drug layer can comprise pyridostigmine bromide,hypromellose, and talc.

In certain embodiments, the seal coat can comprise at least onewater-soluble polymer comprising hypromellose and/or hydroxypropylcellulose.

In certain embodiments, the functional coat can comprise at least onewater-insoluble lipophilic material and, optionally, at least onewater-soluble hydrophilic polymer. In certain embodiments, thefunctional coat can comprise at least one water-insoluble lipophilicpolymer and at least one water-soluble hydrophilic polymer (i.e., a poreformer).

In certain embodiments, the water-insoluble lipophilic material in thefunctional coat/membrane can be selected from the group comprising, butnot limited to, ethyl acrylate and methyl methacrylate copolymer(EUDRAGIT® NE, EUDRAGIT® NM), ammonio methacrylate copolymer (EUDRAGIT®RL PO, EUDRAGIT® RS PO), carnauba wax, stearic acid, ethylcellulose(ETHOCEL™), cellulose acetate, and polyvinyl acetate dispersion(KOLLICOAT® SR). In certain embodiments, the water-soluble hydrophilicpolymer comprises, but is not limited to, polyethylene glycol (PEG 400,PEG 1000, PEG 1450, PEG 3350), hydroxypropyl cellulose, polyvinylpyrolidone (PVP), KOLLIDON® 30, KOLLICOAT® IR, mannitol, andmethylcellulose (METHOCEL™ E3, METHOCEL™ E5, METHOCEL™ E6).

In certain embodiments, the functional coat further can comprise atleast one plasticizer and at least one anti-tacking agent. Usefulanti-tacking agents can include, but are not limited to, silicon dioxide(SYLOID® 244FP), fumed silica (CAB-O-SIL®), talc, kaolin, andcombinations thereof. Useful plasticizers include, but are not limitedto, triethyl citrate, triacetin, polyethylene glycol, propylene glycol,and dibutyl sebacate. In certain embodiments, the plasticizer can betriethyl citrate. In certain embodiments, the plasticizer can be dibutylsebacate.

In certain embodiments, the pellets can be retained in capsules. Incertain embodiments, a composition can consist of pellets consolidatedinto a packed mass for ingestion, even though the packed mass willseparate into individual pellets after ingestion. Conventional methodscan be used for consolidating the pellets in this manner. For example,the pellets can be placed in gelatin capsules known in the art as“hard-filled” capsules and “soft-elastic” capsules. The compositions ofthese capsules and procedures for filling them are known among thoseskilled in drug formulations and manufacture. The encapsulating materialshould be highly soluble so that the particles are freed and rapidlydispersed in the stomach after the capsule is ingested. In certainembodiments, the pellets can be incorporated directly into food assprinkles.

In certain embodiments, the present disclosure provides for apyridostigmine bromide pellet comprising an inert core, a drug layercontaining pyridostigmine bromide over the inert core, and a membraneover the drug layer, wherein the membrane comprises a water-insolublelipophilic polymer and a water-soluble hydrophilic polymer, and whereinthe pellet provides extended release, with minimized initial burstrelease, of pyridostigmine bromide, for at least about 14 hours. Incertain embodiments, the water-insoluble lipophilic polymer of thepellet of the present disclosure is selected from the group consistingof an ethyl acrylate and methyl methacrylate copolymer, an ammoniomethacrylate copolymer, ethylcellulose, cellulose acetate, polyvinylacetate, and mixtures thereof. In certain embodiments, the water-solublehydrophilic polymer of the pellet of the present disclosure is selectedfrom the group consisting of polyethylene glycol, hydroxypropylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polyvinylpyrolidone, methylcellulose, xanthan gum, guar gum, sodium alginate,starch, a copolymer of polyvinyl acetate and polyvinyl pyrolidone, acopolymer of ethylene glycol and propylene glycol, a copolymer ofpolyvinyl alcohol and polyethylene glycol, and mixtures thereof. Incertain embodiments, the pellet of the present disclosure furthercomprises a seal coat between the drug layer and the membrane. Incertain embodiments, the seal coat of the pellet of the presentdisclosure comprises a water-soluble polymer selected from the groupconsisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and mixtures thereof. In certain embodiments, thewater-soluble polymer of the pellet of the present disclosure ishypromellose, hydroxypropyl cellulose, or a mixture thereof.

In certain embodiments, the pellets can comprise from about 100 mg toabout 250 mg, from about 150 mg to about 200 mg, or about 180 mg ofpyridostigmine bromide in a pyridostigmine bromide containing core. Incertain embodiments, the pellets can comprise a seal coat. In certainembodiments, the seal coat can comprise from about 5 mg to about 30 mg,from about 10 mg to about 20 mg, or about 15 mg of hydroxypropylcellulose. In certain embodiments, the seal coat can further comprisefrom about 1 mg to about 10 mg, from about 2 mg to about 5 mg, or about3 mg of talc. In certain embodiments, the pellets can further comprise afunctional coat. The functional coat can comprise from about 10 mg toabout 50 mg, from about 20 mg to about 40 mg, or from about 25 mg toabout 35 mg of ethyl cellulose. In certain embodiments, the functionalcoat can further comprise from about 1 mg to about 10 mg, from about 2mg to about 5 mg, or about 3 mg of triethyl citrate. In certainembodiments, the functional coat can further comprise from about 1 mg toabout 10 mg, from about 2 mg to about 5 mg, or about 3 mg of talc. Incertain embodiments, the functional coat can further comprise from about1 mg to about 10 mg, from about 2 mg to about 5 mg, or about 3 mg ofmethylcellulose.

In certain embodiments, the present disclosure provides for apyridostigmine bromide pellet comprising an inert core, a drug layercontaining pyridostigmine bromide over the inert core, and a membraneover the drug layer, wherein the membrane comprises a water-insolublelipophilic polymer and a water-soluble hydrophilic polymer, and whereinthe pellet provides extended release, with minimized initial burstrelease, of pyridostigmine bromide, for at least about 14 hours. Incertain embodiments, the water-insoluble lipophilic polymer of thepellet of the present disclosure is selected from the group consistingof an ethyl acrylate and methyl methacrylate copolymer, an ammoniomethacrylate copolymer, ethylcellulose, cellulose acetate, polyvinylacetate, and mixtures thereof. In certain embodiments, the water-solublehydrophilic polymer of the pellet of the present disclosure is selectedfrom the group consisting of polyethylene glycol, hydroxypropylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polyvinylpyrolidone, methylcellulose, xanthan gum, guar gum, sodium alginate,starch, a copolymer of polyvinyl acetate and polyvinyl pyrolidone, acopolymer of ethylene glycol and propylene glycol, a copolymer ofpolyvinyl alcohol and polyethylene glycol, and mixtures thereof. Incertain embodiments, the pellet of the present disclosure furthercomprises a seal coat between the drug layer and the membrane. Incertain embodiments, the seal coat of the pellet of the presentdisclosure comprises a water-soluble polymer selected from the groupconsisting of a polyvinyl alcohol-based polymer, methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and mixtures thereof. In certain embodiments, thewater-soluble polymer of the pellet of the present disclosure ishypromellose, hydroxypropyl cellulose, or a mixture thereof.

In certain embodiments, the pellets can comprise from about 20 mg toabout 150 mg, from about 50 mg to about 100 mg, or from about 70 mg toabout 80 mg of pyridostigmine bromide granules in a pyridostigminebromide containing core. In certain embodiments, the pellet can furthercomprise a drug layer. In certain embodiments, the drug layer cancomprise from about 50 mg to about 200 mg, from about 75 mg to about 150mg, or from about 95 mg to about 105 mg of pyridostigmine bromide. Incertain embodiments, the drug layer can further comprise from about 10mg to about 40 mg, from about 15 mg to about 30 mg, or from about 20 mgto about 25 mg of methylcellulose. In certain embodiments, the druglayer can further comprise from about 1 mg to about 10 mg, from about 2mg to about 8 mg, or from about 3 mg to about 5 mg of talc. In certainembodiments, the pellets can further comprise a seal coat. In certainembodiments, the seal coat can comprise from about 5 mg to about 30 mg,from about 10 mg to about 25 mg, or from about 15 mg to about 20 mg ofhydroxypropyl cellulose. In certain embodiments, the seal coat canfurther comprise from about 1 mg to about 10 mg, from about 2 mg toabout 8 mg, or from about 3 mg to about 5 mg of talc. In certainembodiments, the pellets can further comprise a functional coat. Incertain embodiments, the functional coat can comprise from about 10 mgto about 100 mg, from about 25 mg to about 80 mg, or from about 50 mg toabout 75 mg of ethyl cellulose. In certain embodiments, the functionalcoat can further comprise from about 2 mg to about 15 mg, from about 2mg to about 10 mg, or from about 5 mg to about 8 mg of triethyl citrate.In certain embodiments, the functional coat can further comprise fromabout 2 mg to about 15 mg, from about 2 mg to about 10 mg, or from about5 mg to about 8 mg of talc.

In certain embodiments, the pellets can comprise a cellet core. Incertain embodiments, the pellet comprises about 100 mg of cellet core.In certain embodiments, the pellets can further comprise a drug layer.In certain embodiments, the drug layer can comprise from about 100 mg toabout 300 mg, from about 125 mg to about 250 mg, or from about 150 mg toabout 200 mg of pyridostigmine bromide. In certain embodiments, the druglayer can further comprise from about 10 mg to about 60 mg, from about20 mg to about 50 mg, or from about 30 to about 40 mg of ethylcellulose. In certain embodiments, the drug layer can further comprisefrom about 1 mg to about 10 mg, from about 2 mg to about 7 mg, or fromabout 3 mg to about 5 mg of dibutyl sebacate. In certain embodiments,the drug layer can further comprise from about 1 mg to about 15 mg, fromabout 5 mg to about 10 mg, or about 6 mg of talc. In certainembodiments, the pellet can further comprise a seal coat. In certainembodiments, the seal coat can comprise from about 10 mg to about 100mg, from about 10 mg to about 85 mg, from about 50 mg to about 75 mg, orfrom about 15 mg to about 20 mg of methylcellulose. In certainembodiments, the seal coat can further comprise from about 1 mg to about10 mg, from about 2 mg to about 8 mg, or from about 3 mg to about 5 mgof talc. In certain embodiments, the pellet can further comprise afunctional coat. In certain embodiments, the functional coat cancomprise from about 20 mg to about 120 mg, from about 30 mg to about 100mg, from about 45 to about 85 mg, or from about 50 mg to about 75 mg ofethylcellulose. In certain embodiments, the functional coat can furthercomprise from about 5 mg to about 30 mg, from about 10 mg to about 25mg, or from about 12 mg to about 18 mg of dibutyl sebacate. In certainembodiments, the functional coat can further comprise from about 1 mg toabout 20 mg, from about 5 mg to about 15 mg, or from about 7 mg to about13 mg of talc. In certain embodiments, the functional coat can furthercomprise from about 0.5 mg to about 5 mg, from about 1 mg to about 4 mg,or from about 2 mg to about 3 mg of fumed silica. In certainembodiments, the functional coat can further optionally comprise fromabout 0.5 mg to about 15 mg, from about 1 mg to about 10 mg, or fromabout 1.5 mg to about 2.5 mg of methylcellulose. In certain embodiments,the functional coat can further optionally comprise from about 20 mg toabout 150 mg, from about 50 mg to about 120 mg, or from about 75 mg toabout 100 mg of cellulose acetate. In certain embodiments, thefunctional coat can further optionally comprise from about 5 mg to about40 mg, from about 10 mg to about 25 mg, or from about 15 mg to about 20mg of polyethylene glycol.

6.3. Methods of Making

In certain embodiments, the present disclosure provides extended releasepyridostigmine compositions suitable for maintaining stable plasmaconcentrations, with minimized initial burst release/dose dumping, ofpyridostigmine bromide. In certain embodiments, the compositions of thedisclosure can provide extended release of pyridostigmine bromide for atleast about 16 hours. The extended release pyridostigmine compositionsof the disclosure can include matrix tablets, and pellets suitable fordosing in capsules, sachets, and as sprinkles on food. In certainembodiments, the pyridostigmine compositions can comprisegastroretentive tablet compositions providing extended release ofpyridostigmine for at least about 16 hours. In certain embodiments,gastroretentive pyridostigmine compositions of the disclosure aresuitable for once-daily administration.

In certain embodiments, the pyridostigmine compositions of thedisclosure can be direct compression tablets. The tablets can be made bymixing pyridostigmine bromide, a water-insoluble lipophilic polymer, afiller, a lubricant, and a glidant into a uniform blend; compressing theblend into a tablet core; and coating the tablet core with a functionalcoat/membrane. In certain embodiments, there can be a seal coat betweenthe tablet core and the functional coat. In certain embodiments, thepyridostigmine compositions of the disclosure can include pyridostigminegranules that are made by hot-melt extrusion. In certain embodiments,the hot-melt extruded pyridostigmine granules can be mixed withextragranular excipients into a uniform blend, and the uniform blend canbe compressed into a tablet.

In certain embodiments, the pyridostigmine compositions of thedisclosure can be gastroretentive tablets. The tablets can be made bymixing pyridostigmine bromide, one or more gas-generating agents, anacid, a wicking agent, a filler, and a glidant into a uniform blend;adding lubricant to the resulting blend and compressing the blend into atablet core; coating the tablet core with a seal coat comprising aqueousdispersion of hydroxypropyl cellulose; coating the seal-coated tabletswith a functional coat comprising a plasticizer, and at least one ofethyl acrylate and methyl methacrylate copolymer (EUDRAGIT® NE,EUDRAGIT® NM), and an ammonio methacrylate copolymer (EUDRAGIT® RL PO,EUDRAGIT® RS PO). In certain embodiments, the functional coat cancomprise a plasticizer, and an ammonio methacrylate copolymer (EUDRAGIT®RL PO, EUDRAGIT® RS PO). In certain embodiments, the gastroretentivetablets can be further coated with an IR drug layer comprisingpyridostigmine bromide and a binder, using a perforated pan coater.

In certain embodiments, the pyridostigmine compositions of thedisclosure can comprise pyridostigmine pellets suitable for dosing incapsules, sachets, and as sprinkles on food. In certain embodiments, thepellets can comprise a pyridostigmine bromide core. In certainembodiments, the pellets can comprise a cellet. In certain embodiments,the pellet cores (e.g., pyridostigmine bromide cores or cellets) arefurther drug-layered with pyridostigmine bromide. In certainembodiments, the pellets are made by coating the pyridostigmine bromidecore with a seal coat comprising a water-soluble hydrophilic polymer;coating the seal-coated pellets with a functional coat comprising aplasticizer, a water-insoluble lipophilic polymer that is insoluble inphysiological fluids, and a pore former comprising a water-solublehydrophilic polymer. In certain embodiments, the pyridostigmine bromidecores are further drug-layered with pyridostigmine bromide. In certainembodiments, various solvents used in processes of the disclosureinclude, but are not limited to, water, methanol, ethanol, acetone,isopropyl alcohol, and mixtures thereof. In certain embodiments, thesolvent is a mixture of acetone and water, a mixture of ethanol andisopropyl alcohol, a mixture of acetone and isopropyl alcohol, a mixtureof isopropyl alcohol and water, or a mixture of water, ethanol, andisopropyl alcohol. In certain embodiments, the solvent is a mixture ofacetone and water. In certain embodiments, the ratio of solvent andwater ranges from about 70:30 to about 99:1. In certain embodiments, theratio of acetone and water is about 70:30, about 75:25, about 80:20,about 85:15, about 90:10, about 95:5, or intermediate ranges therein.

6.4. Methods of Treatment

In certain embodiments, the disclosure provides a method for treatingmyasthenia gravis (MG), postoperative bowel bloating, and urinaryretention in a patient. In certain embodiments, the disclosure providesa method for treating or preventing organophosphorus or nerve gaspoisoning or injuries. In certain embodiments, the disclosure provides amethod for treating dementia, including Alzheimer's disease. The methodscomprise administering to a patient or a person in need thereof, anextended release pyridostigmine bromide dosage form of the disclosure.The dosage form is suitable for once- or twice-daily administration. Incertain embodiments, the dosage forms of the present disclosure areadministered QD as a single dosage unit. In certain embodiments, thecompositions of the disclosure are administered QD as multiple dosageunits (e.g., two, three, or four dosage units). In certain embodiments,the dose strength and dosing frequency is determined based on thecondition being treated and the severity of the condition.

In certain embodiments, the disclosure provides a method for improvingpatient compliance by administering extended release pyridostigminebromide dosage forms of the disclosure, wherein the compositions providean extended release, with no initial dose dumping compared to marketedextended release pyridostigmine products. In certain embodiments, theextended release pyridostigmine dosage forms of the disclosure improvepatient compliance by including an IR drug layer that provides a drugplasma concentration sufficient to overcome the lag time inpyridostigmine release seen without application of an IR portion, andsufficient to provide instant therapeutic effects, with reduced oreliminated GI side effects; the extended release portion providescontrolled extended release of the drug for a period of at least about14 hours.

In certain embodiments, the disclosure provides a method for improvingpatient compliance by administering an extended release pyridostigminebromide dosage forms of the disclosure, wherein the extended releasedosage forms will allow for reduced frequency of administration of thecomposition. In certain embodiments, the dosage forms of the disclosurereduce initial burst release/minimize initial burst release whileproviding a therapeutically effective amount of pyridostigmine bromidefor periods of about 12 hours to about 24 hours.

In certain embodiments, the disclosure provides methods for improvingpatient compliance by administering, to a patient or a subject in needthereof, an extended release pyridostigmine bromide dosage forms of thedisclosure, reducing or minimizing initial burst release ofpyridostigmine bromide, and providing the desired therapeutic effectwith minimal side effects including nausea, vomiting, diarrhea,abdominal cramps, fasciculations, increased peristalsis, increasedsalivation, increased bronchial secretions, miosis, and diaphoresis. Themethods comprise administering to the patient an extended releasepyridostigmine bromide dosage form of the disclosure. The extendedrelease dosage forms of the disclosure are suitable for once- ortwice-daily administration.

In certain embodiments, the present disclosure provides for atherapeutic method for treating myasthenia gravis, comprising orallyadministering to a subject in need thereof a single QD gastroretentivepyridostigmine bromide tablet, wherein the tablet provides an extendedrelease, with minimized initial burst release, of pyridostigmine bromidefor up to about 24 hours, and wherein the minimized initial burstrelease comprises release of not more than 20% of pyridostigmine bromidewithin two hours of dissolution in a dissolution medium. In certainembodiments, the dissolution medium comprises 50 mM acetate buffer with100 mM NaCl. In certain embodiments, the present disclosure provides fora method for reducing GI side effects in a patient consuming apyridostigmine composition, the method comprising administering to thepatient a gastroretentive pyridostigmine composition comprising anextended release portion and an immediate release portion as a singletablet/day, wherein the composition provides an extended release, with areduced initial burst release, of pyridostigmine bromide for at leastabout 14 hours, and wherein the reduced initial burst release comprisesrelease of between 20% and 35% of pyridostigmine bromide within twohours of dissolution of the composition into a dissolution medium.

In certain embodiments, the present disclosure provides for a method forimproving patient compliance in a patient consuming a pyridostigminecomposition, the method comprising administering to the patient agastroretentive pyridostigmine composition comprising an extendedrelease portion and an immediate release portion as a single tablet/day,wherein the composition provides an extended release, with a reducedinitial burst release, of pyridostigmine bromide for at least about 14hours

7. EXAMPLES

The following examples illustrate the disclosure in a nonlimitingmanner. Unless indicated to the contrary, the numerical parameters setforth herein can vary depending upon the desired properties sought to beobtained by the present disclosure.

Example 1: Pyridostigmine Bromide Matrix Tablet Compositions (180 mg)

The present example provides various formulations for pyridostigminebromide tablets as outlined in Table 1 and Table 2. Seven differenttablets were prepared.

TABLE 1 Formulation of Matrix Tablets Tablet Tablet Tablet Tablet Tablet1 2 3 4 5 Ingredients (mg) (mg) (mg) (mg) (mg) Pyridostigmine 180.0180.0 180.0 180.0 180.0 bromide Stearic acid — 180.0 — 20.00 20.00Carnauba wax — — — 160.00 80.00 Ethylcellulose — — — — — (ETHOCEL ™)Silicon dioxide 180.0 — 180.0 — 80.00 (SYLOID ® 244FP) Fumed silica —20.00 20.00 20.00 20.00 (CAB-O-SIL ®) Mannitol (PARTECK ®) 100.0 100.0100.0 100.0 100.0 Magnesium stearate 5.00 5.00 5.00 5.00 5.00 CoreTablet Weight 465.0 485.0 485.0 485.0 485.0 Functional Coat Celluloseacetate 40.40 41.73 41.73 41.73 41.73 Polyethylene 2.02 2.08 2.08 2.082.08 glycol (PEG 3350) Methylcellulose 4.004 4.173 4.173 4.173 4.173(METHOCEL ™ E5) Solvent* acetone:water (95:5) Total Tablet Weight 511.42532.98 532.98 532.98 532.98 *Removed during process

TABLE 2 Formulation of Matrix Tablets Tablet 6** Tablet 7 Ingredients(mg) (mg) Pyridostigmine bromide 150.00 180.00 Stearic acid — 90.00Ethylcellulose (ETHOCEL ™) 100.00 — Silicon dioxide (SYLOID ® 244FP)20.00 — Fumed silica (CAB-O-SIL ®) — 10.00 Mannitol (PARTECK ®) 100.00100.00 Magnesium stearate 5.00 5.00 Core Tablet Weight 375.00 385.00Functional Coat Cellulose acetate 62.50 33.40 Polyethylene glycol (PEG3350) 6.25 1.67 Methylcellulose (METHOCEL ™ E5) 6.25 3.34 Solvent*acetone:water (95:5) Total Weight 450.00 423.41 *Removed during process**Tablet 6 can have an IR coat of 30 mg of pyridostigmine bromide

Tablets 1-5 and Tablet 7 contain 180 mg of pyridostigmine bromide andinclude 10% coating weight gain of uncoated tablet. Tablets 1-5 and 6 donot contain ethylcellulose. Tablet 6 contains 150 mg of pyridostigminebromide, ethylcellulose, and 20% coating weight gain of uncoated tablet.Tablets 1-7 were made according to the following general procedure.

Manufacturing Procedure:

-   1. A uniform blend of pyridostigmine, stearic acid, carnauba wax,    ethylcellulose, silicon dioxide, fumed silica, mannitol, and    magnesium stearate was made as per Tablets 1-7.-   2. For each blend, the drug and the excipients were taken in a    V-blender and mixed for about 5 minutes.-   3. Required amount of blend was filled into the die and then    compressed as tablet compositions.-   4. Cellulose acetate and methylcellulose were added to a stainless    steel container charged with an acetone and water mixture in a ratio    of 95:5 and mixed to obtain a clear solution.-   5. Polyethylene glycol 3350 was added to the solution from step #4    and mixed for not less than about 30 minutes.-   6. The tablets from step #3 were taken in a coating pan and coated    with the solution from step #5 until the target weight gain was    attained.

FIG. 2 depicts a schematic representation of pyridostigmine matrixtablets, with and without an immediate release drug layer.

Example 2: Pyridostigmine Bromide Gastroretentive Tablet Compositions

The present Example provides various formulations for pyridostigminebromide gastroretentive tablets as outlined in Table 3.

TABLE 3 Formulation of Pyridostigmine Bromide Tablets Tablet TabletTablet Tablet Tablet 8 9 10 11 12 (mg/ (mg/ (mg/ (mg/ (mg/ Ingredientsdose) dose) dose) dose) dose Pyridostigmine 180.0 180.0 180.0 135.0135.0 bromide Succinic acid, 50.0 50.0 50.0 80.0 80.0 NF-micronizedSodium bicarbonate 50.00 50.0 50.0 55.0 55.0 Calcium carbonate 125.0125.0 125.0 65.0 65.0 Crospovidone 100.0 100.0 100.0 200.0 100.0PARTECK(R) 200 233.0 233.0 233.0 153.0 253.0 BENECEL ™ 200.0 300.0 200.0— 100.0 K4M PH DC BENECEL ™ — — 25.0 — — K200M METHOCEL ™ — — — 300.0200.0 K100 Prem LVCR CAB-O-SIL ® 4.00 4.00 4.00 4.00 4.00 Magnesiumstearate 8.00 8.00 8.00 8.00 8.00 Total weight 950.0 1050.0 975.0 1000.01000.0 Seal Coat Hydroxypropyl 33.33 33.33 33.33 — — cellulose Talc 3.333.33 3.33 — — Triethyl citrate 3.33 3.33 3.33 — — Solvent* — — — — —acetone:water (95:5) Functional Coat EUDRAGIT ® 148.15 148.15 148.15148.15 148.15 RL PO Triethyl citrate 22.22 22.22 22.22 22.22 22.22 Talc29.63 29.63 29.63 29.63 29.63 Solvent* — — — — — acetone:water (95:5)Over Coat OPADRY ® 15.00 15.00 15.00 — — white Total weight 1205.001305.00 1230.00 1200.0 1200.0 *Removed during process

Tablets 8-10 contain 180 mg of pyridostigmine, 50 mg of succinic acid,50 mg of sodium bicarbonate, 125 mg of calcium carbonate, and BENECELK4M-DC. Tablet 10 further contains BENECEL 200M. Tablets 11-12 contain135 mg of pyridostigmine bromide, and 80 mg of succinic acid, 55 mg ofsodium bicarbonate, and 65 mg of calcium carbonate. Further, Tablet 11contains METHOCEL K100 Premium LVCR and Tablet 12 contains a mixture ofMETHOCEL K100 Premium LVCR and BENECEL K4M PH DC. Tablets 8-12 were madeaccording to the following general procedure.

Manufacturing Procedure:

A. Core tablets

-   1. Pyridostigmine, succinic acid, sodium bicarbonate, calcium    carbonate, crospovidone, PARTECK® 200, BENECEL™ K4M-DC, BENECEL™    K200M, METHOCEL™ K100 Premium LVCR, and CAB-O-SIL®, as per Tablets    8-12, were sieved through filter #20 and mixed to obtain a uniform    blend.-   2. Magnesium stearate was sieved through sieve #30 and mixed with    the uniform blend from step #1.-   3. The resulting blend from step #2 was compressed to obtain    pyridostigmine tablet cores.

B. Seal Coating

-   1. Hydroxypropyl cellulose, triethyl citrate, and talc were added to    a mixture of acetone and water (95:5) in a stainless steel container    and mixed to form a uniform dispersion.-   2. Tablet cores 8-10 were seal coated using a perforated pan coater    with an inlet air temperature of 25° C.-60° C. at a product    temperature of 30-45° C.-   3. The coated tablet cores were dried in the coating pan.

C. Functional Coating and Over Coat

-   1. EUDRAGIT® RL PO was added to acetone and water mixture (95:5) and    mixed to obtain a clear solution.-   2. To the solution from step #1, triethyl citrate was added and    mixed for at least 5 minutes.-   3. To the solution from step #2, talc was added and mixed for at    least 60 minutes to obtain a homogeneous dispersion.-   4. The homogeneous dispersion from step #3 was sprayed onto the seal    coated tablet cores 8-10 and tablet cores without seal coat, e.g.,    Tablet cores 11-12.-   5. The coated tablets from step #4 were dried in a coating pan.-   6. An orifice was laser drilled in the coated tablets from step #5    such that the orifice passed through various coating layers.-   7. Weighed quantity of opadry white was added into the required    amount of purified water. The suspension was mixed until a uniform    dispersion was formed.-   8. The functional coated tablets from step #6 were further coated    with the dispersion from step #7 in a perforated coating pan with    inlet air temperature at 25°−45° C.-   9. The coated tablets from step #8 were dried in a pan to a moisture    content below 1.5%, as measured by loss on drying at 105° C.

FIG. 4 provides a comparison of dissolution profiles of pyridostigminebromide gastroretentive Tablets 8, 9 and 10, using USP I-custombasket-dissolution apparatus, in 50 mM of pH 4.5 acetate buffer, at 100RPM. FIG. 4 demonstrates that Tablets 8-10 provide extended release,with minimized initial burst release, of pyridostigmine bromide for aperiod of about 22 hours.

Example 3: Pyridostigmine Bromide Pellet Composition ComprisingPyridostigmine Bromide Granule Core

The present Example provides for a pyridostigmine bromide pelletcomposition comprising a pyridostigmine bromide core as outlined inTable 4.

TABLE 4 Formulation of Pyridostigmine Bromide Pellet Pellet 1Ingredients mg/dose Pyridostigmine bromide granules 180.00 Seal CoatHydroxypropyl cellulose (KLUCEL ™) 15.00 Talc 3.00 Functional coat Ethylcellulose (ETHOCEL ™ 20 cp) 30.40 Triethyl citrate 3.00 Talc 3.00METHOCEL ™ E5 Premium LV 3.00 Solvent* ethanol:water (90:10) TotalWeight 237.40 *Removed during process

Pellet 1 contains pyridostigmine bromide granule as pellet core, and afunctional coat comprising ethyl cellulose and triethyl citrate. Pellet1 was made according to the following general procedure.

Manufacturing Procedure: A. Seal Coating

-   1. Hydroxypropyl cellulose was added to dehydrated alcohol in a    stainless steel container and mixed to form a uniform solution.-   2. To the dispersion from step #1, the purified water was added and    mixed until a clear solution formed.-   3. To the solution from step #2, triethyl citrate was added and    mixed for not less than about 15 minutes.-   4. To the solution from step #3, talc was added and mixed for not    less than about 30 minutes to form a homogenous dispersion.-   5. Pyridostigmine bromide granules were coated using a Wurster fluid    bed coater with an inlet air temperature of 40-50° C., and    sufficient air volume for fluidization. When the product temperature    reached 30° C., the dispersion from step #4 was sprayed onto the    granules while maintaining the product temperature of 25-35° C. and    sufficient air volume for the fluidization, until the target coating    weight gain was achieved.

B. Functional Coating

-   1. Ethyl cellulose and METHOCEL™ E5 Premium LV were added to    dehydrated alcohol in a stainless steel container and mixed for    about 1 hour to form a uniform dispersion.-   2. To the dispersion from step #1, water was added and mixed to    obtain a homogeneous dispersion.-   3. To the dispersion from step #2, TEC was added and mixed for not    less than about 15 minutes.-   4. To the dispersion from step #3, talc was added and mixed for not    less than about 30 minutes to obtain a uniform dispersion.-   5. Seal coated pyridostigmine bromide granules (procedure A, above)    were taken in a Wurster chamber and coated with the dispersion from    step #4, until target coating weight gain was achieved.

Example 4: Pyridostigmine Bromide Pellet Composition ComprisingPyridostigmine Bromide Granule Core and Drug Layer ContainingPyridostigmine Bromide

The present Example provides for a pyridostigmine bromide pelletcomposition comprising a pyridostigmine bromide granule core and a druglayer containing pyridostigmine bromide. Two different pellets wereprepared as outlined in Table 5.

TABLE 5 Formulation of Pyridostigmine Bromide Pellet Pellet 2 Pellet 3Ingredients mg/dose mg/dose Pyridostigmine bromide granules 78.16 78.16Drug Layer Pyridostigmine bromide 101.84 101.84 METHOCEL ™ E5 Premium LV20.36 20.36 Talc 4.07 4.07 Solvent* ethanol:water (85:15) Seal CoatHydroxypropyl cellulose (KLUCEL ™ LF) 17.04 17.04 Talc 3.40 3.40Solvent* acetone:water (95:5) Functional Coat Ethyl cellulose (ETHOCEL ™20 cp) 56.20 — Ethyl cellulose (ETHOCEL ™ 45 cp) — 74.90 Triethylcitrate 5.60 7.50 Talc 5.60 7.50 Solvent* ethanol:water (90:10) TotalWeight 292.27 314.77 *Removed during process

Pellets 2 and 3 contain pyridostigmine bromide granules as pellet coreand a pyridostigmine bromide drug layer over the pellet core. Pellet 2contains 30 wt % functional coat, of the seal coated pellet core, andPellet 3 contains 40 wt % functional coat, of the seal coated pelletcore. Pellets 2 and 3 were made according to the following generalprocedure.

Manufacturing Procedure: A. Drug Layering

-   1. Pyridostigmine bromide and METHOCEL™ Premium LV were added to a    mixture of ethanol and water (85:15) and mixed for not less than    about 60 minutes to obtain a solution.-   2. To the solution from step #1, talc was added and mixed for not    less than about 30 minutes to obtain a uniform dispersion.-   3. Pyridostigmine bromide granules were coated using a Wurster fluid    bed coater, with an inlet air temperature of about 30-40° C., and    sufficient air volume for fluidization.-   4. When the product temperature reached 30° C., the dispersion from    step #3 was sprayed onto the pyridostigmine bromide granules while    maintaining the product temperature of 25-35° C. and sufficient air    volume for the fluidization, until the target coating weight gain    was achieved.

B. Seal Coating

-   1. Hydroxypropyl cellulose was added to dehydrated alcohol in a    stainless steel container and mixed to form a uniform solution.-   2. To the solution from step #1, the purified water was added and    mixed until a clear solution was obtained.-   3. To the solution from step #2, triethyl citrate was added and    mixed for not less than about 15 minutes.-   4. To the solution from step #3, talc was added and mixed for not    less than about 30 minutes to form a homogenous dispersion.-   5. Pyridostigmine granules were coated using a Wurster fluid bed    coater with an inlet air temperature of 40-50° C., and sufficient    air volume for fluidization. When the product temperature reached    30° C., the dispersion from step #4 was sprayed onto the granules    while maintaining the product temperature of 28-30° C. and    sufficient air volume for the fluidization, until the target coating    weight gain was achieved.

C. Functional Coating

-   1. Ethylcellulose and METHOCEL™ Premium LV were added to dehydrated    alcohol in a stainless steel container and mixed for not less than    about 60 minutes to obtain a uniform dispersion.-   2. To the dispersion from step #1, water was added and mixed for not    less than about 30 minutes to obtain a homogeneous dispersion.-   3. To the dispersion from step #2, TEC was added and mixed for not    less than about 15 minutes.-   4. To the dispersion from step #3, talc was added and mixed for not    less than about 30 minutes to obtain a uniform dispersion.-   5. Seal coated pyridostigmine granules (procedure B) were taken in a    Wurster chamber and coated with the dispersion from step #4, until    target coating weight gain was achieved.

FIG. 1 depicts a schematic representation of pyridostigmine pellets,with and without an immediate release drug layer.

FIG. 5 compares dissolution profiles of pyridostigmine bromide Pellets 2and 3, using USP Apparatus II, in 50 mM of pH 6.8 buffer. FIG. 5demonstrates that pellets containing pyridostigmine bromide granules aspellet core provide fast drug release, irrespective of their functionalcoat weight gain.

Example 5: Pyridostigmine Bromide Pellet Composition Comprising CelletCore

The present Example provides for pyridostigmine bromide pelletcompositions comprising cellet cores. Eight different pellets wereprepared as outlined in Tables 6, 7, and 8.

TABLE 6 Formulation of Pyridostigmine Bromide Pellets Pellet 4 Pellet 5Pellet 6 Ingredients mg/dose mg/dose mg/dose Cellet core (350 μm) 100.00100.00 100.00 Drug Layer Pyridostigmine bromide 150.00 150.00 150.00ETHOCEL ® Standard 20 Premium 30.00 30.00 30.00 Dibutyl Sebacate (DBS)3.00 3.00 3.00 Talc 6.00 6.00 6.00 Solvent* ethanol:water (90:10) Sealcoat METHOCEL ™ E5 Premium LV 72.05 72.05 72.05 Talc 14.41 14.41 14.41Solvent* acetone:water (95:5) NA NA NA Functional coat ETHOCEL ®Standard 20 Premium 44.90 112.2 — Dibutyl sebacate 9.00 22.40 — Talc6.70 16.86 — CAB-O-SIL ® 1.10 2.80 — Cellulose acetate (CA-398-10NF/EP)— — 89.70 PEG 3350 — — 17.90 METHOCEL ™ E5 Premium LV — — 13.50 Solvent*ethanol:water (90:10) q.s. q.s. q.s. Total Weight 437.16 529.72 496.56*Removed during process

TABLE 7 Formulation of Pyridostigmine Bromide Pellets Pellet 7 Pellet 8Ingredients mg/dose mg/dose Cellet core (350 μm) 100.00 100.00 DrugLayer Pyridostigmine bromide 150.00 150.00 ETHOCEL ® Standard 20 Premium30.00 30.00 Dibutyl sebacate (DBS) 3.00 3.00 Talc 6.00 6.00 Solvent*ethanol:water (90:10) Seal coat (6.7% wt) METHOCEL ™ E5 Premium LV 16.2016.20 Talc 3.20 3.20 Solvent* acetone:water (95:5) Functional coatETHOCEL ® Standard 20 Premium 52.30 83.60 Dibutyl sebacate 10.50 16.80Talc 7.80 12.50 METHOCEL ™ E5 Premium LV 5.20 8.40 CAB-O-SIL ® 1.30 3.10Acetone:Water (90:10) Total Weight 385.50 432.80 *Removed during process

TABLE 8 Formulation of Pyridostigmine Bromide Pellets Pellet 9 Pellet 10Pellet 11 Ingredients mg/dose mg/dose mg/dose Cellet core (350/500 μm)100.0 100.0 100.0 Drug Layer Pyridostigmine bromide 180.0 180.0 180.0ETHOCEL ® Standard 20 Premium 36.00 36.00 36.00 Talc 7.20 7.20 7.20Dibutyl Sebacate (DBS) 3.60 3.60 3.60 Solvent* ethanol:water (90:10)Seal Coat METHOCEL ™ E5 Premium LV 19.06 19.06 19.06 Talc 3.82 3.82 3.82Solvent* acetone:water (95:5) Functional Coat ETHOCEL ® Standard 20Premium 56.20 74.94 99.91 Dibutyl Sebacate 11.24 14.99 19.98 Talc 8.4311.24 14.98 METHOCEL ™ E5 Premium LV 1.40 1.87 2.50 CAB-O-SIL ® 1.401.87 2.50 Solvent* ethanol:water (90:10) Total Weight 428.35 454.59489.55 *Removed during process

Pellets 4-11 contain a cellet core coated with a drug layer containingpyridostigmine bromide and a functional coat over the drug layer;Pellets 4 and 5 contain a functional coat comprising ETHOCEL® Standard20 Premium, dibutyl sebacate, and talc; Pellet 6 contains a cellet coreand a functional coat comprising cellulose acetate 398, polyethyleneglycol, and METHOCEL™E5 Premium LV; and Pellets 7-11 contain functionalcoat comprising ETHOCEL® Standard 20 Premium, dibutyl sebacate, talc.Pellets 4-11 were made according to the following general procedure.

Manufacturing Procedure: A. Drug Layering

-   1. Pyridostigmine bromide and ETHOCEL® Standard 20 Premium were    added to a mixture of ethanol and water (90:10) and mixed for not    less than about 60 minutes to obtain a solution, followed by    addition of dibutyl sebacate.-   2. To the solution from step #1, talc was added and mixed for not    less than about 30 minutes to obtain a uniform dispersion.-   3. Cellet core was coated using a Wurster fluid bed coater, with an    inlet air temperature of about 25-40° C., and sufficient air volume    for fluidization. When the product temperature reached 30° C., the    dispersion from step #2 was sprayed onto the cellets while    maintaining the product temperature of 25-30° C. and sufficient air    volume for the fluidization, until the target coating weight gain    was achieved.

B. Seal Coating

-   1. METHOCEL™E5 Premium LV was added to dehydrated alcohol and water    mixture in a stainless steel container and mixed to form a uniform    solution.-   2. To the solution from step #2, talc was added and mixed for not    less than about 30 minutes to obtain a homogeneous dispersion.-   3. Pyridostigmine bromine drug-layered granules (procedure A) were    coated using Wurster fluid bed coater with an inlet air temperature    of 30-35° C., and sufficient air volume for fluidization. When the    product temperature reached 30° C., the dispersion from step #2 was    sprayed onto the drug-layered granules while maintaining the product    temperature of 28-30° C. and sufficient air volume for the    fluidization, until the target coating weight gain was achieved.

C. Functional Coating

-   1. ETHOCEL® Standard 20 Premium or cellulose acetate 398 (as per    Pellets 4-11) was added to dehydrated alcohol and water or acetone    and water mixture in a stainless steel container and mixed for not    less than about 60 minutes to obtain a uniform solution.-   2. To the solution from step #1, METHOCEL™ E5 and DBS were added and    mixed until a clear solution was formed.-   3. To the dispersion from step #2, talc and CAB-O-SIL™ were added,    and mixed for not less than about 30 minutes to obtain a uniform    dispersion.-   4. Seal coated pyridostigmine pellets (Step B) were taken in a    Wurster chamber and coated with the dispersion from step #3, until    target coating weight gain was achieved.

FIG. 6 compares dissolution profiles of pyridostigmine bromide Pellets9-11, using USP Apparatus II, in 50 mM of pH 6.8 buffer.

FIG. 6 demonstrates that Pellets 10 and 11, containing higher functionalcoat weight gain, provide better controlled release of pyridostigminebromide for a period of about 22 hours.

Example 6: Effect of the Presence of Orifice in Functional Coat onRelease Rate of Gastroretentive Pyridostigmine Compositions

The present Example provides for comparison of dissolution profiles oftablets comprising pyridostigmine bromide. Three different tablets wereprepared as outlined in Table 9. Tablets were made with and without anorifice in the functional coat to evaluate the effect an orifice has ondissolution profiles.

TABLE 9 Formulation of Pyridostigmine Bromide Gastroretentive TabletsTablet 8 Tablet 13 Tablet 14 Ingredients (mg/dose) (mg/dose) (mg/dose)Tablet Core Pyridostigmine bromide 180.0 135.0 135.0  Succinic acid 50.080.0 80.0 Sodium bicarbonate 50.0 55.0 55.0 Calcium carbonate 125.0 65.065.0 Crospovidone 100.0 100.0 100.0  PARTECK(R) M200 (D-mannitol) 233.0253.0  253.0 ( BENECEL ™ K4M PH DC 200.0 — 150.0  METHOCEL ™ K100 PremLVCR — 300.0 150.0  CAB-O-SIL ® 4.00 4.00  4.00 Magnesium stearate 8.008.00  8.00 Total Weight 950.0 1000.0 1000.0  Seal Coat Hydroxypropylcellulose 33.33 — — Talc 3.33 — — Triethyl citrate 3.33 — — Solvent*acetone:water (95:5) q.s. — — Functional Coat EUDRAGIT ® RL PO 148.15148.15 148.15 Triethyl citrate 22.22 22.22  22.22 Talc 29.63 29.63 29.63 Solvent* acetone:water (95:5) q.s. q.s. q.s. Over Coat OPADRY ®white 15.0 — — Total Weight 1205.0 1200.0 1200.0  *Removed duringprocess

Tablet 8 contains 180 mg of pyridostigmine, 50 mg of succinic acid, 50mg of sodium bicarbonate, 125 mg of calcium carbonate, and BENECELK4M-DC. Tablets 13 and 14 contain 135 mg of pyridostigmine bromide, 80.0mg of succinic acid, 55.0 mg of sodium bicarbonate, and 65.0 mg ofcalcium carbonate. Further, Tablet 13 contains METHOCEL™ K100 Prem LVCRand Tablet 14 contains a mixture of METHOCEL™ K100 Prem LVCR and BENECELK4M-DC. Tablets 8, 13 and 14, each containing an orifice in fluidcommunication with the pull layer, were made according to the procedureas per Example 2. FIG. 7 compares dissolution profiles of Tablets 8, 13and 14 in about 900 ml of pH 5.0 acetate buffer containing 150 mM NaCl,using USP Apparatus I (Custom Basket), at 100 rpm and 37° C. FIG. 7shows that Tablets 13 and 14 provide 10-15% slower drug release comparedto Tablet 8.

FIG. 8 compares dissolution profiles, of Tablets 13 and 14 containing anorifice/hole in the membrane/functional coat and Tablets 13 and 14without orifice/hole in the membrane/functional coat. The dissolutiontesting was conducted in about 250 ml of pH 3.0 dissolution mediacontaining about 100 mM NaCl, using USP Apparatus III (BIO-DIS), at 25dpm and 37° C. FIG. 8 demonstrates that Tablets 13 and 14 without anyorifice/hole in the functional coat provided reduced drug recoverycompared to the Tablets 8, 13, and 14 containing an orifice/hole in thefunctional coat.

Example 7: Effect of Coating Level of Functional Coat and Presence ofOrifice/Hole in the Functional Coat on Release Rate of GastroretentivePyridostigmine Compositions

The present Example provides for comparison of dissolution profiles oftablets comprising pyridostigmine bromide and various functional coatingcompositions. Three different tablets were prepared as outlined in Table10. The tablets were tested with and without an orifice/in theirfunctional coat.

TABLE 10 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet14 Tablet 14A Ingredients (mg/dose) (mg/dose) (mg/dose) Tablet CorePyridostigmine bromide 180.0 135.0 135.0 Succinic acid 50.0 80.0 80.0Sodium bicarbonate 50.0 55.0 55.0 Calcium carbonate 125.0 65.0 65.0Crospovidone 100.0 100.0 100.0 PARTECK(R) M200 233.0 253.0 253.0BENECEL ™ K4M PH DC 200.0 — 150.0 METHOCEL ™ K100 Prem — 300.0 150.0LVCR CAB-O-SIL ® 4.0 4.00 4.00 Magnesium stearate 8.0 8.00 8.00 TotalWeight 950.0 1000.0 1000.0 Seal Coat Hydroxypropyl Cellulose 33.33 — —Talc 3.33 — — Triethyl citrate 3.33 — — Solvent* acetone:water q.s. — —(95:5) Functional Coat EUDRAGIT ® RL PO 148.15 148.15 185.18 Triethylcitrate 22.22 22.22 27.77 Talc 29.63 29.63 37.03 Solvent* acetone:waterq.s. q.s. q.s. (95:5) Total Weight 1190.0 1200.0 1250.0 *Removed duringprocess

Tablets 8 and 14 contain 200 mg coating weight gain of the functionalcoat and Tablet 14A contains 250 mg coating weight gain of thefunctional coat. Tablets 8, 14, and 14A were made according to theprocedure as per Example 2. FIG. 9 compares dissolution profiles, ofTablets 8, 14, and 14A containing an orifice/hole in the functional coatand Tablets 14 and 14A without orifice/hole in the functional coat. Thedissolution testing was conducted in about 900 ml of pH 5.0 acetatebuffer containing 150 mM NaCl, using USP Apparatus I (Custom Basket), at100 rpm and 37° C. FIG. 9 demonstrates that coating weight gain has nosignificant effect on release rate of the tablets. The figure furtherdemonstrates that tablets with orifice/hole provided significantlyhigher release rate compared to tablets without orifice/hole.

Example 8: Effect of Coating Level of Functional Coat and Presence of anOrifice/Hole in the Functional Coat on Floating Lag Time and VolumeExpansion of Gastroretentive Pyridostigmine Compositions

The present example provides for evaluation of floating lag time andvolume expansion of various tablets comprising pyridostigmine bromide.Eight different tablets were prepared as outlined in Tables 11 and 12with various levels of functional coating. The tablets were tested withand without an orifice in their functional coats.

TABLE 11 Formulation of Pyridostigmine Bromide Tablets Tablet TabletTablet Tablet 8 8A 11 11A (mg/ (mg/ (mg/ (mg/ Ingredients dose) dose)dose) dose) Tablet Core Pyridostigmine 180.0 180.0 135.0 135.0 bromideSuccinic acid 50.0 50.0 80.0 80.0 Sodium bicarbonate 50.0 50.0 55.0 55.0Calcium carbonate 125.0 125.0 65.0 65.0 Crospovidone 100.0 100.0 200.0200.0 PARTECK(R) ® 233.0 233.0 153.0 253.0 M200 BENECEL ™ 200.0 200.0 —150.0 K4M PH DC METHOCEL ™ — — 300.0 150.0 K100 PREM LVCR CAB-O-SIL ®4.00 4.00 4.00 4.00 Magnesium stearate 8.00 8.00 8.00 8.00 Total Weight950.0 950.0 1000.0 1000.0 Seal Coat Hydroxypropyl 33.33 33.33 — —cellulose Talc 3.33 3.33 — — Triethyl citrate 3.33 3.33 — — Solvent*q.s. q.s. — — acetone:water (95:5) Functional Coat EUDRAGIT ® 148.15185.18 148.15 185.18 RL PO Triethyl citrate 22.22 27.77 22.22 27.77 Talc29.63 37.03 29.63 37.03 Solvent* q.s. q.s. q.s. q.s. acetone:water(95:5) Over Coat Opadry white 15.0 15.0 — — Total Weight 1205.0 1255.01200.0 1250.0 *Removed during process

TABLE 12 Formulation of Pyridostigmine Bromide Tablets Tablet 13 Tablet13A Tablet 15 Tablet 15A Ingredients (mg/dose) (mg/dose) (mg/dose)(mg/dose) Tablet Core Pyridostigmine bromide 135.00 135.0 135.0 135.0Succinic acid 80.0 80.0 125.0 125.0 Sodium bicarbonate 55.0 55.0 75.075.0 Calcium carbonate 65.0 65.0 100.0 100.0 Crospovidone 100.0 100.0200.0 200.0 PARTECK(R) ®M200 253.0 253.0 153.0 153.0 BENECEL ™ K4M PH DC— — 100.0 100.0 METHOCEL ™ K100 Prem LVCR 300.0 300.0 100.0 100.0CAB-O-SIL ® 4.00 4.00 4.00 4.00 Magnesium stearate 8.00 8.00 8.00 8.00Total Weight 1000.0 1000.0 1000.0 1000.0 Seal Coat Hydroxypropylcellulose — — — — Talc — — — — Triethyl citrate — — — — Solvent*acetone:water (95:5) — — — — Functional Coat EUDRAGIT ® RL PO 148.15185.18 148.15 185.18 Triethyl citrate 22.22 27.77 22.22 27.77 Talc 29.6337.03 29.63 37.03 Solvent* acetone:water (95:5) q.s. q.s. q.s. q.s. OverCoat OPADRY ® white — — — — Total Weight 1200.0 1250.0 1200.0 1250.0*Removed during process

Tablets 8 and 8A contain 180 mg of pyridostigmine bromide, 50 mg ofsuccinic acid, 50 mg of sodium bicarbonate, 125 mg of calcium carbonate,and a seal coat. Tablets 11 and 11A contain 135 mg of pyridostigminebromide, 80 mg of succinic acid, 55 mg of sodium bicarbonate, and 65 mgof calcium carbonate. Tablets 13 and 13A contain 135 mg ofpyridostigmine bromide, 80 mg of succinic acid, 55 mg of sodiumbicarbonate, and 65 mg of calcium carbonate. Tablets 15 and 15A contain135 mg of pyridostigmine bromide, 125 mg of succinic acid, 75 mg ofsodium bicarbonate, and 100 mg of calcium carbonate. Tablets 8 and 8A donot include a seal coat; Tablets 8/8A and Tablets 13/13A contain 100 mgof crospovidone, and Tablets 11/11A and tablets 15/15A contain 200 mg ofcrospovidone. Tablets 8, 8A, 11, 11A, 13, 13A, 15, and 15A were madeaccording to the procedure as per Example 2. FIG. 10 compares floatinglag time of Tablets 8, 11, 13, and 15, with and without orifice/hole, at200 mg functional coating weight gain, and Tablets 8A, 11A, 13A, and15A, with and without orifice/hole, at 250 mg functional coating weightgain. The flotation studies were performed, using Rotating Bottle methodat 5 rpm and 37° C., in 200 ml of a dissolution medium with pH 4.5comprising 100 mM NaCl. The figure demonstrates that tablets with 200 mgfunctional coating weight gain exhibit shorter lag time compared totablets with 250 mg functional coating weight gain. The figure furtherdemonstrates that Tablets 8/8A containing a seal coat exhibit longerfloating lag time compared to tablets without a seal coat (Tablets11/11A, 13/13A, and 15/15A).

FIG. 11 compares volumetric expansion at flotation of Tablets 8, 11, 13,and 15, with and without orifice/hole, at 200 mg functional coatingweight gain, and Tablets 8A, 11A, 13A, and 15A, with and withoutorifice/hole, at 250 mg functional coating weight gain. The volumeexpansion studies were performed, using Rotating Bottle method at 5 rpmand 37° C., in 200 ml of pH 4.5 dissolution medium containing 10 mM ofNaCl. The figure demonstrates that tablets without orifice/hole exhibithigher volume expansion compared to tablets with orifice/hole.

FIG. 12 compares volumetric expansion, at 90 minutes and at one hour, ofTablets 8, 11, 13, and 15, with and without orifice/hole, at 200 mgfunctional coating weight gain, and Tablets 8A, 11A, 13A, and 15A, withand without orifice/hole, at 250 mg functional coating weight gain. Thevolume expansion studies were performed, using Rotating Bottle method,at 5 rpm and 37° C., in 200 ml of pH 4.5 dissolution medium containing10 mM of NaCl. The figure demonstrates that tablets without orifice/holeexhibit higher volume expansion compared to tablets with orifice/hole.

FIG. 13 compares volumetric expansion and weight gain at 24 hours, ofTablets 8, 11, 13, and 15, with orifice/hole and without orifice/hole,at 200 mg functional coating weight gain. The volume expansion andweight gain studies were performed, using Rotating Bottle method at 5rpm and 37° C., in 200 ml of pH 4.5 dissolution medium containing 100 mMof NaCl. FIG. 13 demonstrates that tablets containing 200 mg ofcrospovidone (e.g., Tablets 11/11-H and 15/15-H) exhibit higher weightupon drying compared with tablets containing 100 mg of crospovidone(e.g., Tablets 8/8-H and 13/13-H).

Example 9: Dissolution Profiles of Gastroretentive PyridostigmineCompositions Using BIO-DIS Method

The present Example provides for measurements of dissolution profiles ofvarious gastroretentive pyridostigmine compositions. Five compositionswere prepared as outlined in Table 13 and tested using BIO-DIS method.

TABLE 13 Formulation of Pyridostigmine Bromide Tablets Tablet TabletTablet Tablet Tablet 8 8B 15 16 17 (mg/ (mg/ (mg/ (mg/ (mg/ Ingredientsdose) dose) dose) dose) dose) Tablet Core Pyridostigmine 180.0 180.0135.0 135.0 135.0 bromide Succinic acid 50.0 50.0 125.0 125.0 85.0Sodium 50.0 50.0 75.0 75.0 56.0 bicarbonate Calcium 125.0 125.0 100.0100.0 67.0 carbonate Crospovidone 100.0 100.0 200.0 200.0 200.0PARTECK^((R)) 233.0 233.0 153.0 153.0 45.0 M200 BENECEL ™ 200.0 200.0100.0 — — K4M PH DC METHOCEL ™ — — 100.0 200.0 400.0 K100 Prem LVCRCAB-O-SIL ® 4.00 4.00 4.00 4.00 4.00 Magnesium 8.00 8.00 8.00 8.00 8.00stearate Total Weight 950.0 950.0 1000.0 1000.0 1000.0 Seal CoatHydroxypropyl 33.33 33.33 — — — cellulose Talc 3.33 3.33 — — — Triethyl3.33 3.33 — — — citrate Solvent* q.s. q.s. — — — acetone:water (95:5)Functional Coat EUDRAGIT ® 148.15 296.3 148.15 148.15 148.15 RL POTriethyl 22.22 44.44 22.22 22.22 22.22 citrate Talc 29.63 59.26 29.6329.63 29.63 Solvent* q.s. q.s. q.s. q.s. q.s. acetone:water (95:5) OverCoat OPADRY ® 15.0 15.0 — — — white Total Weight 1205.0 1405.0 1200.01200.0 1200.0 *Removed during process

Tablets 8, 15, 16, and 17 contain 200 mg functional coating weight gainand Tablet 8B contains 400 mg functional coating weight gain. Tablets 8,8B, 15, 16, and 17 were made according to the procedure as per Example2. FIG. 14 compares dissolution profiles of Tablets 8B, 15, 16, and 17without an orifice/hole and Tablets 8, 8B, 15, 16, and 17 with anorifice/hole. Dissolution studies were performed using BIO-DIS method at20 dpm and 37° C., in 250 ml of pH 3.0 dissolution medium containing 100mM NaCl. FIG. 13 demonstrates that tablets without an orifice/holeexhibit slower drug release compared to tablets with an orifice/hole.

Example 10: Dissolution Profiles of Gastroretentive PyridostigmineCompositions Using USP-I Method

The present Example provides for measurements of dissolution profiles ofvarious gastroretentive pyridostigmine compositions. Three compositionswere prepared as outlined in Table 14 and tested using USP-I method.

TABLE 14 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet18 Tablet 19 Ingredients (mg/dose) (mg/dose) (mg/dose) Tablet CorePyridostigmine bromide 180.0 180.0 180.0 Succinic acid 50.0 125.0 125.0Sodium bicarbonate 50.0 75.0 75.0 Calcium carbonate 125.0 100.0 100.0Crospovidone 100.0 200.0 200.0 PARTECK^((R)) M200 233.0 108.0 108.0BENECEL ® K4M PH DC 200.0 — 100.0 METHOCEL ® K100 Premium — 200.0 100.0LVCR CAB-O-SIL ® 4.00 4.00 4.00 Magnesium stearate 8.00 8.00 8.00 TotalWeight 950.0 1000.0 1000.0 Seal Coat Hydroxypropyl cellulose 33.33 — —Talc 3.33 — — Triethyl citrate 3.33 — — Solvent* acetone:water (95:5)q.s. q.s. q.s. Functional Coat EUDRAGIT ® RL PO 148.15 107.15 107.15Triethyl citrate 22.22 21.42 21.42 Talc 29.63 21.42 21.42 Solvent*acetone:water (95:5) q.s. q.s. q.s. Over Coat OPADRY ® white 15.0 — —Total Weight 1205.0 1150.0 1150.0 *Removed during process

Tablet 8 contains BENECEL® K4M PH DC and 100 mg of crospovidone, Tablet18 contains METHOCEL and 200 mg of crospovidone, and Tablet 19 containsa mixture of METHOCEL™ K100 Premium LVCR, and BENECEL® K4M PH DC, and200 mg of crospovidone. Tablets 8, 18, and 19 were made according to theprocedure as per Example 2. Tablets 8, 18, and 19 were tested fordissolution in about 900 ml of pH 5 dissolution medium, containing 150mM of NaCl, 30 mM of sodium acetate, and 17 mM of acetic acid, using USPApparatus I (Custom Basket), at 100 rpm and 37° C. FIG. 15 demonstratesthat tablets containing 200 mg of crospovidone (Tablets 18 and 19)exhibit faster drug release and better drug recovery compared to Tablet8 containing 100 mg of crospovidone.

Example 11: Dissolution Profiles of Gastroretentive PyridostigmineCompositions Using USP-I Method

The present Example provides for measurements of dissolution profiles ofvarious gastroretentive pyridostigmine compositions. Three compositionswere prepared as outlined in Table 15 and tested using USP-I method.

TABLE 15 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet20 Tablet 21 Ingredients (mg/dose) (mg/dose) (mg/dose) Tablet CorePyridostigmine bromide 180.0 305.0 255.0 Succinic acid 50.0 80.0 80.0Sodium bicarbonate 50.0 55.0 55.0 Calcium carbonate 125.0 65.0 65.0Crospovidone 100.0 100.0 100.0 PARTECK^((R)) M200 233.0 73.00 123.0BENECEL ® K4M PH DC 200.0 150.0 150.0 METHOCEL ® K100 Prem LVCR — 150.0150.0 CAB-O-SIL ® 4.00 10.00 10.00 Magnesium stearate 8.00 12.00 12.00Total Weight 950.0 1000.0 1000.0 Seal Coat- Hydroxypropyl cellulose33.33 — — Talc 3.33 — — Triethyl citrate 3.33 — — Solvent* acetone:water(95:5) q.s. q.s. q.s. Functional Coat EUDRAGIT ® RL PO 148.15 148.15148.15 Triethyl citrate 22.22 22.22 22.22 Talc 29.63 29.63 29.63Solvent* acetone:water (95:5) q.s. q.s. q.s. Over Coat- OPADRY ® white15.0 — — Total Weight 1205.0 1200.0 1200.0 *Removed during process

Tablet 8 contains 200 mg of BENECEL™, Tablets 20 and 21 contain 150 mgeach of BENECEL™ and METHOCEL™ Tablets 8, 20, and 21 were made accordingto the procedure as per Example 2. Tablets 8, 20, and 21 were tested fordissolution in about 900 ml of pH 5.0 buffer containing 150 mM NaCl,using USP Apparatus I (Custom Basket), at 100 rpm and 37° C. FIG. 16demonstrates that tablets containing a mixture of BENECEL and METHOCEL(Tablets 20 and 21) provide more controlled release compared to Tablet 8containing BENECEL only.

Example 12: Dissolution Profiles of Gastroretentive PyridostigmineCompositions Using USP-I Method

The present Example provides for measurements of dissolution profiles ofvarious gastroretentive pyridostigmine compositions. Three compositionswere prepared as outlined in Table 15 and tested using USP-I method.

TABLE 16 Formulation of Pyridostigmine Bromide Tablets Tablet 8 Tablet22 Tablet23 Ingredients (mg/dose) (mg/dose) (mg/dose) Tablet CorePyridostigmine bromide 180.0 135.0 135.0 Succinic acid 50.0 80.0 80.0Sodium bicarbonate 50.0 55.0 55.0 Calcium carbonate 125.0 65.0 65.0Crospovidone 100.0 100.0 100.0 PARTECK^((R)) M200 233.0 249.0 299.0Oxide Pigment Black — — 12.0 BENECEL ® K4M PH DC 200.0 150.0 150.0METHOCEL ® K100 Prem LVCR — 150.0 150.0 CAB-O-SIL ® 4.00 10.00 10.00Magnesium stearate 8.00 12.00 12.00 Total Weight 950.0 1006.0 1068.0Seal Coat Hydroxypropyl cellulose 33.33 — — Talc 3.33 — — Triethylcitrate 3.33 — — Solvent* acetone:water (95:5) q.s. — — Functional CoatEUDRAGIT ® RL PO 148.15 148.15 148.15 Triethyl citrate 22.22 22.22 22.22Talc 29.63 29.63 29.63 Solvent* acetone:water (95:5) q.s. q.s. q.s. SealCoat OPADRY ® II, Clear — — 10.0 Purified water, USP — — q.s. Drug LayerPyridostigmine bromide — — 45.0 Hydroxypropyl cellulose — — 9.0Dehydrated alcohol, USP — — q.s. Over Coat OPADRY ® white 15.0 — 40.0Total Weight 1205.0 1206.0 1372.0 *Removed during process

Tablet 23 contains an immediate release drug layer. Tablet 8 contains200 mg of BENECEL® K4M PH DC, Tablets 22 and 23 contain 150 mg each ofBENECEL® K4M PH DC and METHOCEL® K100 Prem LVCR. Tablets 8, 22, and 23were made according to the procedure as per Example 2. Tablet 23 wasfurther coated with a seal coat, an IR drug layer coat, and an over coatas follows:

D. Seal Coat

-   1. Hydroxypropyl cellulose, triethyl citrate, and talc were added to    a mixture of acetone and water (95:5) in a stainless steel container    and mixed to form a uniform dispersion.-   2. Tablet core 23 with a functional coat was seal coated with the    dispersion from Step 1, using a perforated pan coater with an inlet    air temperature of 25° C.-60° C. at a product temperature of 30-45°    C.

E. IR Drug Layer

-   1. Seal coated pyridostigmine bromide tablets from Step D were    further coated with a solution of pyridostigmine bromide,    hydroxypropyl cellulose in dehydrated alcohol, using a perforated    pan coater with an inlet air temperature of 25° C.-60° C. at a    product temperature of 30-45° C.

F. Over Coat

-   1. Weighed quantity of OPADRY® white was added to a required amount    of purified water and mixed to obtain a uniform dispersion.-   2. The tablets with IR drug layer from Step E were further coated    with the dispersion from step #1 in a perforated coating pan with    inlet air temperature at 25° C.-45° C.-   3. The coated tablets from step #2 were dried in the coating pan to    a moisture content of below 1.5%.

Tablets 8, 22, and 23 were tested for dissolution in about 900 ml of pH5.0 buffer containing 150 mM of NaCl, using USP Apparatus I (CustomBasket), at 100 rpm and 37° C. FIG. 17 demonstrates that the tabletcontaining an immediate release drug layer (Tablet 23) eliminates lagtime compared to tablets that do not contain an immediate release druglayer (Tablets 8 and 22).

Example 13: Additional Gastroretentive Pyridostigmine Compositions

The present Example provides for various gastroretentive pyridostigminecompositions. Ten different compositions were prepared as outlined inTables 17 and 18.

TABLE 17 Formulation of Pyridostigmine Bromide Tablets Tablet TabletTablet Tablet Tablet 24 25 26 27 28 (mg/ (mg/ (mg/ (mg/ (mg/ Ingredientsdose) dose) dose) dose) dose) Tablet Core Pyridostigmine 305.0 305.0305.0 255.0 255.0 bromide Succinic acid 80.0 80.0 80.0 80.0 80.0 Sodiumbicarbonate 55.0 55.0 55.0 55.0 55.0 Calcium carbonate 65.0 65.0 65.065.0 65.0 Crospovidone 100.0 100.0 100.0 100.0 100.0 PARTECK^((R)) 73.0— — 123.0 — M200 BENECEL ® 150.0 186.50 236.5 150.0 211.5 K4M PH DCMETHOCEL ® 150.0 186.5 236.5 150.0 211.5 K100 Prem LVCR CAB-O-SIL ®10.00 10.00 10.00 10.00 10.00 Magnesium stearate 12.00 12.00 12.00 12.0012.00 Total Weight 1000.0 1000.0 1100.0 1000.0 1000.0 Seal CoatHydroxypropyl — — — — — cellulose Talc — — — — — Triethyl citrate — — —— — Solvent* — — — — — acetone:water (95:5) Functional Coat EUDRAGIT ®148.15 148.15 148.15 148.15 148.15 RL PO Triethyl citrate 22.22 22.2222.22 22.22 22.22 Talc 29.63 29.63 29.63 29.63 29.63 Solvent* q.s. q.s.q.s. q.s. q.s. acetone:water (95:5) Over Coat OPADRY ® — — — — — whiteTotal Weight 1200.0 1200.0 1300.0 1200.0 1200.0

TABLE 18 Formulation of Pyridostigmine Bromide Tablets Tablet TabletTablet Tablet Tablet 29 30 31 32 33 (mg/ (mg/ (mg/ (mg/ (mg/ Ingredientsdose) dose) dose) dose) dose) Tablet Core Pyridostigmine 70.0 155.0205.0 305.0 100.0 bromide Succinic acid 80.0 80.0 80.0 80.0 80.0 Sodium55.0 55.0 55.0 55.0 55.0 bicarbonate Calcium 65.0 65.0 65.0 65.0 65.0carbonate Crospovidone 100.0 100.0 100.0 100.0 100.0 PARTECK^((R)) 308.0223.0 173.0 — 278.0 M200 BENECEL ® 150.0 150.0 150.0 150.0 150.0 K4M PHDC METHOCEL ® 150.0 150.5 150.0 223.0 150.0 K100 Prem LVCR CAB-O-SIL ®10.00 10.00 10.00 10.00 10.0 Magnesium 12.00 12.00 12.00 12.00 12.0stearate Total Weight 1000.0 1000.5 1000.0 1000.0 1000.0 Seal Coat-Hydroxypropyl — — — — — cellulose Talc — — — — — Triethyl citrate — — —— — Solvent* — — — — acetone:water (95:5) Functional Coat EUDRAGIT ®148.15 148.15 148.15 148.15 148.15 RL PO Triethyl 22.22 22.22 22.2222.22 22.22 citrate Talc 29.63 29.63 29.63 29.63 29.63 Solvent* q.s.q.s. q.s. q.s. q.s. acetone:water (95:5) Over Coat OPADRY ® — — — — —white Total Weight 1200.0 1200.5 1200.0 1200.0 1200.0 *Removed duringprocess

Tablets 24-26, and 32 contain 305 mg of pyridostigmine bromide; Tablets27 and 28 contain 255 mg of pyridostigmine bromide, Tablet 29 contains70 mg of pyridostigmine bromide, Tablet 30 contains 155 mg ofpyridostigmine bromide, Tablet 31 contains 205 mg of pyridostigminebromide, and Tablet 33 contains 100 mg of pyridostigmine bromide.Tablets 24, 27, 29-31, and Tablet 33 contain 150 mg each of BENECEL® K4MPH DC and METHOCEL® K100 Premium LVCR, Tablet 25 contains 186.5 mg eachof BENECEL® K4M PH DC and METHOCEL® K100 Premium LVCR, Tablet 26contains 236.5 mg each of BENECEL® K4M PH DC and METHOCEL® K100 PremiumLVCR, Tablet 28 contains 211.5 mg each of BENECEL® K4M PH DC andMETHOCEL® K100 Premium LVCR, and Tablet 32 contains 150.0 mg of BENECEL®K4M PH DC and 223.0 mg of METHOCEL® K100 Premium LVCR. Tablets 24-32were made according to the procedure as per Example 2. Tablet 33 is madeaccording to the procedure as per Example 2.

Example 14: Gastroretentive Pyridostigmine Compositions with IR DrugLayer

The present Example provides for gastroretentive pyridostigminecompositions that comprise instant release drug layer. Three differentcompositions were prepared as outlined in Table 19.

TABLE 19 Formulation of Pyridostigmine Bromide Tablets Tablet 34Ingredients (with hole) Tablet 35 Tablet 36 Tablet Core Pyridostigminebromide 135.0 135.0 70.00 Succinic acid 80.0 80.0 80.0 Sodiumbicarbonate 55.0 55.0 55.0 Calcium carbonate 65.0 65.0 65.0 Crospovidone100.0 100.0 100.0 PARTECK^((R)) M200 235.5 231.0 278.0 Oxide PigmentBlack 7.5 12.0 12.0 BENECEL ® K4M PH DC 150.0 150.0 150.0 METHOCEL ®K100 Prem 150.0 150.0 150.0 LVCR CAB-O-SIL ® 10.00 10.00 10.0 Magnesiumstearate 12.00 12.00 12.0 Total Weight 1000.0 1000.0 982.0 Seal Coat-1Hydroxypropyl cellulose — — Talc — — Triethyl citrate — — Solvent*acetone:water — — (95:5) Functional Coat EUDRAGIT ® RL PO 148.15 148.15148.15 Triethyl citrate 22.22 22.22 22.22 Talc 29.63 29.63 29.63Solvent* acetone:water q.s. q.s. q.s. (95:5) Seal Coat-2 OPADRY ® II,Clear 10.0 10.0 10.0 Purified water, USP q.s. q.s. q.s. Drug LayerPyridostigmine bromide 45.0 45.0 30.0 Hydroxypropyl cellulose 9.0 9.09.0 Dehydrated alcohol, USP q.s. q.s. q.s. Over Coat OPADRY ® White 40.040.0 40.0 Total Weight 1304.0 1304.0 1271.0 *Removed during process

Tablets 34 and 35 contain an immediate release drug layer containing 45mg of pyridostigmine bromide and an extended release portion/tablet corecontaining 135 mg of pyridostigmine bromide. Tablet 36 contains animmediate release drug layer containing 30 mg of pyridostigmine bromideand an extended release portion/tablet core containing 70 mg ofpyridostigmine bromide. Tablets 34-36 contain 150 mg each of BENECEL®K4M PH DC and METHOCEL® K100 Prem LVCR. Tablets 34 and 36 contain alaser drilled hole in the functional coat and Tablet 35 is without ahole. Tablets 34 and 35 were made as per Tablet 23 in Example 12. Tablet36 is made as per Tablet 23 in Example 12.

Example 15: Oral Bioavailability of Pyridostigmine for Tablet 34

A single dose pharmacokinetic (PK) study was conducted in healthyvolunteers under fed conditions to evaluate the PK performance ofextended release compositions of the disclosure using Tablet 34. Anopen-label, balanced, nonrandomized, single-dose, two-treatment, one-waycrossover, comparative bioavailability study was conducted in 15 normal,healthy, adult, human subjects under high-fat high-calorie breakfastconditions and under low fat-low calorie conditions.

Pharmacokinetic parameters for pyridostigmine are summarized in Table20.

TABLE 20 Pharmacokinetics Results of Pyridostigmine Mean ± SD (CV %) (N= 15) Pharmacokinetic LF-LC HF-HC parameters (units) (Condition I)(Condition II) C_(max) (ng/mL) 42.178 ± 9.890 45.073 ± 6.094 (23.448)(13.520) AUC_(0-t) (ng· hr/mL) 670.921 ± 287.971 735.1391 ± 173.317(42.922) (23.576) AUC0-inf (ng · hr/mL) 684.726 ± 292.086 749.674 ±174.634 (42.657) (23.295) T_(max) (hr)* 7.10 ± 3.80 11.0 ± 2.77 (53.55)(25.19) K_(el) (hr−1) 0.15 ± 0.03 0.15 ± 0.03 (18.90) (22.02) t_(1/2)(hr) 4.77 ± 1.03 4.70 ± 1.06 (21.65) (22.52) AUC Extrapolated (%) 2.209± 1.383 2.084 ± 1.657 (62.610) (79.549)

The data from this study (Table 20/FIG. 20) FIG. 20 demonstrates thatTablet 34 provides a therapeutic plasma concentration of pyridostigminefor at least about 22 hours.

Example 16: Oral Bioavailability of Pyridostigmine for Tablet 35(Gastroretentive Dosage Form without Hole)

A single dose pharmacokinetic (PK) study was conducted in healthyvolunteers under fed conditions to evaluate the PK performance ofextended release compositions of the disclosure using Tablet 35. Anopen-label, balanced, nonrandomized, single-dose, two-treatment, one-waycrossover, comparative bioavailability study was conducted in 15 normal,healthy, adult, human subjects under high-fat high-calorie breakfastconditions and under low fat-low calorie conditions.

Pharmacokinetic parameters for pyridostigmine are summarized in Table21.

TABLE 21 Pharmacokinetics Results of Pyridostigmine Mean ± SD (CV %) (N= 15) Pharmacokinetic LF-LC HF-HC parameters (units) (Condition I)(Condition II) C_(max) (ng/mL) 47.444 ± 12.070 43.204 ± 13.455 (25.440)(31.144) AUC_(0-t) (ng · hr/mL) 628.282 ± 322.601 761.807 ± 297.513(51.346) (39.054) AUC0-inf (ng · hr/mL) 635.600 ± 336.928 643.820 ±161.166 (53.009) (25.033) T_(max) (hr)* 8.10 ± 6.25 15.44 ± 4.92 (77.14)(31.85) K_(el) (hr−1) 0.14 ± 0.04 0.15 ± 0.05 (27.80) (31.12) t_(1/2)(hr) 5.23 ± 1.61 5.20 ± 2.03 (30.77) (39.15) AUC Extrapolated (%) 2.654± 2.429 3.621 ± 4.396 (91.528) (121.392)

The data from this study (Table 21/FIG. 21) demonstrate that Tablet 35provides a therapeutic plasma concentration of pyridostigmine for atleast about 22 hours.

1. A gastroretentive dosage form comprising a core, and a permeableelastic membrane comprising at least one orifice and surrounding thecore, wherein the core comprises pyridostigmine or a pharmaceuticallyacceptable salt thereof, a gas-generating agent, and a swellablewater-soluble hydrophilic polymer, and wherein the permeable elasticmembrane comprises at least one copolymer of ethyl acrylate, methylmethacrylate, and trimethylammonioethyl methacrylate chloride.
 2. Thedosage form of claim 1, wherein the dosage form further comprises awicking agent selected from the group consisting of crospovidone;croscarmellose sodium; sodium starch glycolate; low-substitutedhydroxypropyl cellulose; a mixture of mannitol, crospovidone, andpolyvinyl acetate; a coprocessed blend of mannitol, starch,crospovidone, croscarmellose sodium, colloidal silica, and silica;microcrystalline cellulose; alginic acid; and mixtures thereof.
 3. Thedosage form of claim 2, wherein the wicking agent is crospovidone. 4.The dosage form of claim 2, wherein the wicking agent is present in anamount of from about 5 wt % to about 25 wt %, based on the total weightof the core.
 5. The dosage form of claim 1, wherein the core furthercomprises an acid selected from the group consisting of succinic acid,citric acid, acetic acid, malic acid, fumaric acid, stearic acid,tartaric acid, boric acid, benzoic acid, or mixtures thereof.
 6. Thedosage form of claim 5, wherein the acid is succinic acid.
 7. The dosageform of claim 5, wherein the acid is present in an amount of from about0 wt % to about 20 wt %, based on the total weight of the core.
 8. Thedosage form of claim 1, wherein the gas generating agent is selectedfrom the group consisting of carbonate salts and bicarbonate salts ofalkali and alkaline earth metals.
 9. The dosage form of claim 1, whereinthe gas generating agent is selected from the group consisting of sodiumbicarbonate, sodium carbonate, magnesium carbonate, and/or calciumcarbonate, and mixtures thereof.
 10. The dosage form of claim 9, whereinthe gas generating agent is a mixture of sodium bicarbonate and calciumcarbonate.
 11. The dosage form of claim 1, wherein the gas generatingagent is present in an amount of from about 5 wt % to about 50 wt %,based on the total weight of the core.
 12. The dosage form of claim 1,wherein the core further comprises a glidant selected from the groupconsisting of talc, colloidal silicon dioxide, magnesium trisilicate,powdered cellulose, starch, tribasic calcium phosphate, and mixturesthereof.
 13. The dosage form of claim 12, wherein the glidant is presentin an amount of from about 0.1 wt % to about 2 wt %, based on the totalweight of the core.
 14. The dosage form of claim 1, wherein theswellable water-soluble hydrophilic polymer is selected from the groupconsisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose,methyl cellulose, a polyethylene oxide polymer, a carbomer, sodiumalginate, and mixtures thereof.
 15. The dosage form of claim 14, whereinthe swellable water-soluble hydrophilic polymer is hydroxypropylmethylcellulose.
 16. The dosage form of claim 15, wherein the swellablewater-soluble hydrophilic polymer is hydroxypropyl methylcellulose(BENECEL™ K4M PH DC) and hydroxypropyl methylcellulose (METHOCEL™ K100Premium LVCR).
 17. The dosage form of claim 15, wherein the swellablewater-soluble hydrophilic polymer is hydroxypropyl methylcellulose(BENECEL™ K4M PH DC) or hydroxypropyl methylcellulose (METHOCEL™ K100Premium LVCR).
 18. The dosage form of claim 15 wherein the hydroxypropylmethylcellulose is present in an amount of from about 5 wt % to about 35wt %, based on the total weight of the core.
 19. The dosage form ofclaim 1, wherein the core comprises from about 50 mg to about 400 mg ofpyridostigmine or a pharmaceutically acceptable salt thereof.
 20. Thedosage form of claim 1, wherein the core further comprises mannitol. 21.The dosage form of claim 20, wherein the mannitol is present in anamount of from about 1 wt % to about 40 wt %, based on the total weightof the core.
 22. The dosage form of claim 1, wherein the copolymer ispresent in an amount of from about 70 wt % to about 95 wt %, based onthe total weight of the permeable elastic membrane.
 23. The dosage formof claim 1, wherein the permeable elastic membrane further comprises aplasticizer selected from the group consisting of triethyl citrate,triacetin, polyethylene glycol, propylene glycol, dibutyl sebacate, andmixtures thereof.
 24. The dosage form of claim 23, wherein theplasticizer is present in an amount of from about 5 wt % to about 25 wt%, based on the total weight of the permeable elastic membrane.
 25. Thedosage form of claim 23, wherein the membrane further comprises ananti-tacking agent selected from the group consisting of talc, colloidalsilicon dioxide, magnesium trisilicate, powdered cellulose, starch,tribasic calcium phosphate, or mixtures thereof.
 26. The dosage formclaim 25, wherein the anti-tacking agent is present in an amount of fromabout 5 wt % to about 30 wt %, based on the total weight of thepermeable elastic of the membrane.
 27. The dosage form of claim 1,wherein the dosage form further comprises an immediate release druglayer comprising pyridostigmine or a pharmaceutically acceptable saltthereof.
 28. The dosage form of claim 27, wherein the immediate releasedrug layer comprises from about 10 mg to about 100 mg of pyridostigmineor a pharmaceutically acceptable salt thereof.
 29. The dosage form ofclaim 1, wherein the dosage form further comprises a seal coat betweenthe core and the permeable elastic membrane.
 30. The dosage form ofclaim 29, wherein the seal coat comprises a water-soluble polymerselected from the group consisting of polyvinyl alcohol-based polymer(OPADRY® white), methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and mixtures thereof.
 31. Agastroretentive dosage form comprising an immediate release portion andan extended release portion, wherein the immediate release portioncomprises an immediate release drug layer comprising pyridostigmine or apharmaceutically acceptable salt thereof, wherein the extended releaseportion comprises a core, and a permeable elastic membrane comprising atleast one orifice and_surrounding the core, wherein the core comprisespyridostigmine or a pharmaceutically acceptable salt thereof, agas-generating agent, and a swellable_water-soluble hydrophilic polymer,and wherein the permeable elastic membrane comprises a copolymer basedon ethyl acrylate, methyl methacrylate, and trimethylammonioethylmethacrylate chloride.
 32. The dosage form of claim 31, wherein the corefurther comprises an acid selected from the group consisting of succinicacid, citric acid, acetic acid, malic acid, fumaric acid, stearic acid,tartaric acid, boric acid, benzoic acid, or mixtures thereof.
 33. Thedosage form of claim 31, wherein the core further comprises a wickingagent selected from the group consisting of crospovidone; croscarmellosesodium; sodium starch glycolate; low-substituted hydroxypropylcellulose; a mixture of mannitol, crospovidone, and polyvinyl acetate; acoprocessed blend of mannitol, starch, crospovidone, croscarmellosesodium, colloidal silica, and silica; microcrystalline cellulose;alginic acid; and mixtures thereof.
 34. The dosage form of claim 31,wherein the permeable elastic membrane further comprises a plasticizerselected from the group consisting of triethyl citrate, triacetin,polyethylene glycol, propylene glycol, dibutyl sebacate, and mixturesthereof.
 35. A method of treating Myasthenia Gravis, the methodcomprising orally administering to a person in need thereof an extendedrelease gastroretentive dosage form comprising pyridostigmine or apharmaceutically acceptable salt thereof, wherein the dosage formcomprises a core comprising pyridostigmine or a pharmaceuticallyacceptable salt thereof and a permeable elastic membrane comprising atleast one orifice and surrounding the core, wherein the permeableelastic membrane comprises at least one copolymer of ethyl acrylate,methyl methacrylate, and trimethylammonioethyl methacrylate chloride,wherein the dosage form releases about 35 wt % or less of pyridostigmineor a pharmaceutically acceptable salt thereof, within two hours ofdissolution of the dosage form in 900 ml of a dissolution mediumcomprising 50 mM of pH 5 acetate buffer and 150 mM NaCl, measured usingUSP Apparatus I at 100 rpm and 37° C.
 36. A method of treating orpreventing organophosphorus or nerve gas poisoning or injuries, themethod comprising orally administering to a person in need thereof anextended release gastroretentive dosage form comprising pyridostigmineor a pharmaceutically acceptable salt thereof, wherein the dosage formcomprises a core comprising pyridostigmine or a pharmaceuticallyacceptable salt thereof and a permeable elastic membrane comprising atleast one orifice and surrounding the core, wherein the permeableelastic membrane comprises at least one copolymer of ethyl acrylate,methyl methacrylate, and trimethylammonioethyl methacrylate chloride,wherein the dosage form releases about 35 wt % or less of pyridostigmineor a pharmaceutically acceptable salt thereof, within two hours ofdissolution of the dosage form in 900 ml of a dissolution mediumcomprising 50 mM of pH 5 acetate buffer and 150 mM NaCl, measured usingUSP Apparatus I at 100 rpm and 37° C.